U.S. patent application number 13/063856 was filed with the patent office on 2011-09-22 for glycoside derivatives and uses thereof.
This patent application is currently assigned to NOVARTIS AG. Invention is credited to Debnath Bhuniya, Suresh Eknath Kurhade, P. Venkata Palle, Dumbala Srinivas Reddy.
Application Number | 20110230403 13/063856 |
Document ID | / |
Family ID | 41665165 |
Filed Date | 2011-09-22 |
United States Patent
Application |
20110230403 |
Kind Code |
A1 |
Palle; P. Venkata ; et
al. |
September 22, 2011 |
GLYCOSIDE DERIVATIVES AND USES THEREOF
Abstract
The present invention relates to compounds of formula I
##STR00001## and pharmaceutically acceptable salts, to formulations
and uses of the compounds of formula (I) in the treatment of
metabolic disorders.
Inventors: |
Palle; P. Venkata; (Pune,
IN) ; Reddy; Dumbala Srinivas; (Andhra Pradesh,
IN) ; Kurhade; Suresh Eknath; (Maharashtra, IN)
; Bhuniya; Debnath; (West Bengal, IN) |
Assignee: |
NOVARTIS AG
Basel
CH
|
Family ID: |
41665165 |
Appl. No.: |
13/063856 |
Filed: |
September 17, 2009 |
PCT Filed: |
September 17, 2009 |
PCT NO: |
PCT/EP2009/062054 |
371 Date: |
May 12, 2011 |
Current U.S.
Class: |
514/6.5 ; 514/23;
514/7.2; 536/116; 536/120; 536/53; 536/54 |
Current CPC
Class: |
A61P 3/04 20180101; A61P
19/06 20180101; A61P 7/02 20180101; A61P 9/12 20180101; C07D 309/10
20130101; A61P 3/10 20180101; A61P 3/06 20180101; A61P 43/00
20180101; A61P 3/08 20180101 |
Class at
Publication: |
514/6.5 ;
536/116; 514/23; 536/120; 536/53; 536/54; 514/7.2 |
International
Class: |
A61K 38/28 20060101
A61K038/28; C07H 7/04 20060101 C07H007/04; A61K 31/7034 20060101
A61K031/7034; A61K 31/7064 20060101 A61K031/7064; A61K 31/7056
20060101 A61K031/7056; A61K 31/706 20060101 A61K031/706; A61K 38/26
20060101 A61K038/26; A61P 3/10 20060101 A61P003/10; A61P 3/06
20060101 A61P003/06 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 19, 2008 |
IN |
2201/DEL/08 |
Claims
1. A compound of formula I: ##STR00102## or a pharmaceutically
acceptable salt thereof, wherein Rings A and B are independently
C.sub.6-10aryl, C.sub.3-7cycloalkyl, heteroaryl or heterocyclic;
L.sub.1 is --S(O).sub.p--, --N(R.sup.3)--, or --(CH.sub.2).sub.n--,
provided that L.sub.1 is not --N(R.sup.3)-- when X is --O--;
L.sub.2 is --(CH.sub.2).sub.n--O--(CH.sub.2).sub.m--,
--S(O).sub.p--, --N(R.sup.3)--, --Si(R')(R'')--,
--(C(R')(R'')).sub.n--, --(CH.sub.2).sub.nC(O)(CH.sub.2).sub.m--,
--(CH.sub.2).sub.nC(O)NR.sup.3(CH.sub.2).sub.m--,
--(CH.sub.2).sub.nNR.sup.3C(O)(CH.sub.2).sub.m--,
--C.sub.2-6alkenyl-, --C(O) C.sub.2-6alkenyl-,
--N(R.sup.3)C(O)N(R.sup.3)--, --N(R.sup.3)SO.sub.2--, or
--SO.sub.2N(R.sup.3)--; V is halogen, OR.sup.1b or hydrogen; with
the proviso that, when V is --OR.sup.1b, Y is C.sub.6-10aryl,
L.sub.1 is bond, L.sub.2 is --CH.sub.2--, rings A and B are phenyl,
then Y is not unsubstituted aryl or an aryl that is substituted
exclusively with halogen, C.sub.1-6haloalkyl,
C.sub.1-6perhaloalkyl, C.sub.1-6alkoxy, C.sub.1-6haloalkoxy,
C.sub.1-6perhaloalkoxy or cyano as substituents; t is an integer
from 1-4; m, for each occurrence, is independently, 0 or an integer
from 1-4; n, for each occurrence, is independently, 0 or an integer
from 1-4; p, for each occurrence, is independently, 0 or an integer
from 1-2; R' and R'', for each occurrence, are independently
hydrogen, halogen, C.sub.1-6alkyl, or C.sub.1-6perhaloalkyl or
taken together form a cyclic ring which may optionally have
heteroatoms selected from O, N or S; R.sup.1, R.sup.1a and R.sup.1b
are independently selected from hydrogen, C.sub.1-6alkyl,
C.sub.6-10arylC.sub.1-4 alkyl, --C(O)C.sub.6-10aryl or
--C(O)C.sub.1-6alkyl; R.sup.2 and R.sup.2a, for each occurrence,
are independently halogen, hydroxy, C.sub.1-4hydroxylalkyl, cyano,
--NR.sup.4R.sup.5, --CH.sub.2NR.sup.4R.sup.5, C.sub.1-4alkyl,
C.sub.3-7cycloalkyl, C.sub.1-4alkoxy, C.sub.3-7cycloalkoxy,
--S(O).sub.pR.sup.3, --S(O).sub.2NR.sup.4R.sup.5,
--OS(O).sub.2R.sup.3, --C(O)R.sup.3, --C(O)OR.sup.3,
--CH.sub.2C(O)OR.sup.3, --C(O)NR.sup.4R.sup.5,
--CH.sub.2C(O)NR.sup.4R.sup.5, --NR.sup.3C(O)NR.sup.4R.sup.5,
--NR.sup.3C(O)OR.sup.3, C.sub.1-6 haloalkyl, C.sub.1-6
perhaloalkyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkylC.sub.1-4alkyl, C.sub.6-10aryl,
C.sub.6-10arylC.sub.1-4alkyl, C.sub.6-10aryloxy, heterocyclyl,
heterocyclylC.sub.1-4alkyl, heteroaryl, heteroarylC.sub.1-4alkyl,
heteroaryloxy, or heterocycloxy; R.sup.3 is hydrogen,
C.sub.1-6alkyl, C.sub.3-7 cycloalkyl, C.sub.6-10aryl, heteroaryl,
--NR.sup.4R.sup.5 or heterocyclyl; q, for each occurrence, is
independently 0 or an integer from 1-3; Y is C.sub.6-10aryl,
C.sub.3-7cycloalkyl, heteroaryl, or heterocyclic, each of which may
be optionally substituted; X is S(O).sub.p or O; R.sup.4 and
R.sup.5, for each occurrence, are each independently hydrogen,
C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl,
C.sub.3-7cycloalkylC.sub.1-4alkyl, C.sub.6-10arylC.sub.1-4alkyl,
C.sub.6-10aryl, heteroaryl, heteroarylC.sub.1-4alkyl, heterocyclyl,
or heterocyclylC.sub.1-4alkyl, or R.sup.4 and R.sup.5 taken
together may form a monocyclic or a bicyclic ring system which may
be saturated, partially saturated or aromatic and may optionally
have additional heteroatoms selected from O, N or S, the said ring
system may further be optionally substituted; R.sup.6 and R.sup.7,
for each occurrence, are independently hydrogen, C.sub.1-6alkyl,
C.sub.1-6 hydroxyalkyl, C.sub.6-10aryl,
C.sub.6-10arylC.sub.1-4alkyl, C.sub.3-7cycloalkyl, heterocyclyl,
heterocyclylC.sub.1-4alkyl, heteroaryl or heteroarylC.sub.1-4alkyl;
or R.sup.6 and R.sup.7 taken together may form a spiro, monocyclic
or a bicyclic ring system which may be saturated or partially
saturated and may optionally have additional heteroatoms selected
from O, N or S, the said ring system may further be optionally
substituted; wherein when a group is optionally substituted, the
substituents are selected from the group consisting of hydroxyl,
cyano, nitro, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, C.sub.2-6alkenyloxy, C.sub.2-6alkynyloxy, halogen,
C.sub.1-6haloalkyl, C.sub.1-6perhaloalkyl, C.sub.1-6-alkylcarbonyl,
(CH.sub.2).sub.n--COOR.sup.3, amino, C.sub.1-6-alkylamino,
di-C.sub.1-6-alkylamino, aminocarbonyl,
C.sub.1-6-alkylaminocarbonyl, di-C.sub.1-6-alkylaminocarbonyl,
C.sub.1-6-alkylcarbonylamino,
C.sub.1-6-alkylcarbonyl(C.sub.1-6-alkyl)amino,
C.sub.1-6alkoxycarbonylamino, C.sub.1-6-alkylsulfonylamino,
C.sub.1-6-alkylsulfonyl(C.sub.1-6-alkyl)amino, C.sub.1-6alkylthio,
C.sub.1-6-alkylsulfanyl, C.sub.1-6-alkylsulfonyl, aminosulfonyl,
C.sub.1-6-alkylaminosulfonyl and di-C.sub.1-6alkylaminosulfonyl,
aminocarbonylC.sub.1-6alkyl,
C.sub.1-6alkylaminocarbonylC.sub.1-6alkyl,
di-C.sub.1-6alkylaminocarbonylC.sub.1-6alkyl,
sulfanylC.sub.1-6alkyl, C.sub.1-6alkylsulfanylC.sub.1-6alkyl,
sulfinylC.sub.1-6alkyl, C.sub.1-6alkylsulfinylC.sub.1-6alkyl,
sulfonylC.sub.1-6alkyl, C.sub.1-6alkylsulfonylC.sub.1-6alkyl,
cycloalkyl, C.sub.6-10aryl (such as a phenyl), heterocyclyl,
heteroaryl, heterocyclylcarbonyl, pyrrolidinocarbonyl,
azetidinocarbonyl, cycloalkylcarbonylamino,
cyclopropylcarbonylamino, cyclopentycarbonylamino,
cyclohexylcarbonylamino, C.sub.6-10arylcarbonylamino, and
phenylcarbonylamino, wherein each of the aforementioned groups may
be optionally substituted by one or more halogen, C.sub.1-6alkyl,
hydroxyl, oxo, C.sub.1-6-alkoxy, amino, C.sub.1-6-alkylamino,
di-C.sub.1-6-alkylamino or cyano.
2. The compound according to claim 1, wherein the compound is
represented by formula (II) or (III): ##STR00103## or a
pharmaceutically acceptable salt thereof, wherein, R.sup.2 and
R.sup.2a, for each occurrence, are independently selected from
halogen, hydroxy, C.sub.1-4 hydroxylalkyl, cyano,
--NR.sup.4R.sup.5, --CH.sub.2NR.sup.4R.sup.5, C.sub.1-4 alkyl,
C.sub.3-7 cycloalkyl, C.sub.1-4 alkoxy, --S(O).sub.pR.sup.3,
--OS(O).sub.pR.sup.3, --C(O)R.sup.3, --C(O)OR.sup.3,
--CH.sub.2C(O)OR.sup.3, --C(O)NR.sup.4R.sup.5,
--CH.sub.2C(O)NR.sup.4R.sup.5, --NR.sup.3C(O)NR.sup.4R.sup.5,
--NR.sup.3C(O)OR.sup.3, C.sub.1-6 haloalkyl, C.sub.1-6
perhaloalkyl, C.sub.6-10aryloxy, heterocyclyl and heteroaryl; p,
for each occurrence, is independently 0, 1 or 2; q, for each
occurrence, is independently 1, 2, or 3; and Y is optionally
substituted C.sub.6-10aryl or an optionally substituted
heteroaryl.
3. The compound according to claim 1, wherein the compound is
represented by formula (IV) or (V) ##STR00104## or a
pharmaceutically acceptable salt thereof, wherein, R.sup.2 and
R.sup.2a, for each occurrence, are independently selected from
halogen, hydroxy, C.sub.1-4 hydroxylalkyl, cyano,
--NR.sup.4R.sup.5, --CH.sub.2NR.sup.4R.sup.5, C.sub.1-4 alkyl,
C.sub.3-7 cycloalkyl, C.sub.1-4 alkoxy, --S(O).sub.pR.sup.3,
--OS(O).sub.pR.sup.3, --C(O)R.sup.3, --C(O)OR.sup.3,
--CH.sub.2C(O)OR.sup.3, --C(O)NR.sup.4R.sup.5,
--CH.sub.2C(O)NR.sup.4R.sup.5, --NR.sup.3C(O)NR.sup.4R.sup.5,
--NR.sup.3C(O)OR.sup.3, C.sub.1-6 haloalkyl, C.sub.1-6
perhaloalkyl, C.sub.6-10aryloxy, heterocyclyl and heteroaryl; p,
for each occurrence, is independently 0, 1 or 2; q, for each
occurrence, is independently 1, 2, or 3; and Y is optionally
substituted C.sub.6-10aryl or an optionally substituted
heteroaryl.
4. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein Y is C.sub.6-10aryl or
heteroaryl.
5. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein Y is substituted phenyl.
6. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein Y is ##STR00105## R.sup.10 is
independently halogen, hydroxy, C.sub.1-4 hydroxylalkyl, cyano,
--NR.sup.16R.sup.17, oxo (.dbd.O), --CH.sub.2NR.sup.16R.sup.17,
C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, C.sub.1-4 alkoxy,
--S(O).sub.pR.sup.18, --OS(O).sub.2R.sup.18, --C(O)R.sup.18,
--C(O)OR.sup.18, --CH.sub.2C(O)OR.sup.18, --C(O)NR.sup.16R.sup.17,
--CH.sub.2C(O)NR.sup.16R.sup.17, --NR.sup.18C(O)NR.sup.16R.sup.17,
--NR.sup.18C(O)R.sup.18, --NR.sup.18C(O)OR.sup.18,
--CH.sub.2NR.sup.16C(O)OR.sup.18,
--CH.sub.2NR.sup.16C(O)NR.sup.16R.sup.17,
--CH.sub.2NR.sup.16S(O).sub.pR.sup.18,
--S(O).sub.2NR.sup.16R.sup.17, C.sub.1-6 haloalkyl, C.sub.1-6
perhaloalkyl, C.sub.6-10aryloxy, heterocyclyl, heteroaryl; R.sup.18
is hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.6-10aryl,
heteroaryl, or heterocyclyl; R.sup.16 and R.sup.17 are
independently hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl,
C.sub.6-10aryl(C.sub.1-4)alkyl, C.sub.6-10aryl, heteroaryl,
heteroaryl(C.sub.1-4)alkyl, heterocyclyl,
heterocyclyl(C.sub.1-4)alkyl or R.sup.16 and R.sup.17 taken
together may form a monocyclic or a bicyclic ring system which may
be saturated, partially saturated or aromatic and may optionally
have additional heteroatoms selected from O, N or S, the said ring
system may further be optionally substituted; p, for each
occurrence, is independently 0, 1 or 2; and w is 0, or an integer
from 1-4.
7. The compound according to claim 6, or a pharmaceutically
acceptable salt thereof, wherein Y is ##STR00106## ##STR00107##
8. The compound according to claim 6, or a pharmaceutically
acceptable salt thereof, wherein Y is ##STR00108## ##STR00109##
9. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein Y is ##STR00110## ##STR00111##
10. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein Y is ##STR00112##
11. (canceled)
12. A pharmaceutical composition, comprising: a compound according
to claim 1, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable excipient or carrier.
13. A method of treating diabetes, comprising: administering a
compound according to claim 1, or a pharmaceutically acceptable
salt thereof, to a subject in need thereof.
14. A method of treating a disease or condition mediated by
inhibition of sodium D-glucose cotransporter in a mammal,
comprising: administering to the mammal in need thereof a
therapeutically effective amount of a compound according to claim
1, or a pharmaceutically acceptable salt thereof.
15. The method according to claim 14, wherein the disease or
condition is metabolic syndrome, Syndrome X, diabetes, insulin
resistance, decreased glucose tolerance, non-insulin-dependent
diabetes mellitus, Type II diabetes, Type I diabetes, diabetic
complications, a body weight disorder, weight loss, body mass index
or a leptin related disease.
16. The method according to claim 15, wherein the metabolic
syndrome is dyslipidemia, obesity, insulin resistance,
hypertension, microalbuminemia, hyperuricaemia, or
hypercoagulability.
17. A pharmaceutical composition comprising a therapeutically
effective amount of the compound of claim 1, or a pharmaceutically
acceptable salt thereof, in combination with a therapeutically
effective amount of insulin, an insulin derivative, an insulin
mimetic, an insulin secretagogue, an insulinotropic sulfonylurea
receptor ligand, a PPAR ligand, an insulin sensitizer, a biguanide,
an alpha-glucosidase inhibitor; GLP-1, a GLP-1 analog, a GLP-1
mimetic, a DPPIV inhibitor, an HMG-CoA reductase inhibitor, a
squalene synthase inhibitor, an FXR ligand, an LXR ligand,
cholestyramine, a fibrate, nicotinic acid, or aspirin.
18-20. (canceled)
Description
[0001] The invention relates to compounds which have an inhibitory
effect on the sodium-dependent glucose cotransporter SGLT and their
use in therapy.
[0002] This disclosure relates to a series of novel glycoside
derivatives, their polymorphs, stereoisomers, prodrugs, solvates,
pharmaceutically acceptable salts and formulations thereof. The
disclosure also relates to the process for preparation of
substituted glycoside derivatives along with their sodium-D-glucose
cotransporter (SGLT) inhibition effects, which are beneficial for
the prophylaxis, management, treatment, control of progression, or
adjunct treatment of diseases and/or medical conditions where the
inhibition of SGLT would be beneficial, such as diabetes (including
Type-I and Type-II), obesity, dyslipidemia, insulin resistance, and
other metabolic syndrome, and/or diabetes-related complications
including retinopathy, nephropathy, neuropathy, ischemic heart
disease, arteriosclerosis, .beta.-cell dysfunction, and as
therapeutic and/or prophylactic agents for obesity.
[0003] Diabetes mellitus is a metabolic disorder characterized by
recurrent or persistent hyperglycemia (high blood glucose) and
other signs, as distinct from a single disease or condition.
Glucose level abnormalities can result in serious long-term
complications, which include cardiovascular disease, chronic renal
failure, retinal damage, nerve damage (of several kinds),
microvascular damage and obesity.
[0004] Type 1 diabetes, also known as Insulin Dependent Diabetes
Mellitus (IDDM), is characterized by loss of the insulin-producing
.beta.-cells of the islets of Langerhans of the pancreas leading to
a deficiency of insulin. Type-2 diabetes previously known as
adult-onset diabetes, maturity-onset diabetes, or Non-Insulin
Dependent Diabetes Mellitus (NIDDM)--is due to a combination of
increased hepatic glucose output, defective insulin secretion, and
insulin resistance or reduced insulin sensitivity (defective
responsiveness of tissues to insulin).
[0005] Chronic hyperglycemia can also lead to onset or progression
of glucose toxicity characterized by decrease in insulin secretion
from .beta.-cell, insulin sensitivity; as a result diabetes
mellitus is self-exacerbated [Diabetes Care, 1990, 13, 610]
[0006] Chronic elevation of blood glucose level also leads to
damage of blood vessels. In diabetes, the resultant problems are
grouped under "microvascular disease" (due to damage of small blood
vessels) and "macrovascular disease" (due to damage of the
arteries). Examples of microvascular disease include diabetic
retinopathy, neuropathy and nephropathy, while examples of
macrovascular disease include coronary artery disease, stroke,
peripheral vascular disease, and diabetic myonecrosis.
[0007] Diabetic retinopathy, characterized by the growth of
weakened blood vessels in the retina as well as macular edema
(swelling of the macula), can lead to severe vision loss or
blindness. Retinal damage (from microangiopathy) makes it the most
common cause of blindness among non-elderly adults in the US.
Diabetic neuropathy is characterized by compromised nerve function
in the lower extremities. When combined with damaged blood vessels,
diabetic neuropathy can lead to diabetic foot. Other forms of
diabetic neuropathy may present as mononeuritis or autonomic
neuropathy. Diabetic nephropathy is characterized by damage to the
kidney, which can lead to chronic renal failure, eventually
requiring dialysis. Diabetes mellitus is the most common cause of
adult kidney failure worldwide. A high glycemic diet (i.e., a diet
that consists of meals that give high postprandial blood sugar) is
known to be one of the causative factors contributing to the
development of obesity.
[0008] Type 2 diabetes is characterized by insulin resistance
and/or inadequate insulin secretion in response to elevated glucose
level. Therapies for type 2 diabetes are targeted towards
increasing insulin sensitivity (such as TZDs), hepatic glucose
utilization (such as biguanides), directly modifying insulin levels
(such as insulin, insulin analogs, and insulin secretagogues),
increasing incretin hormone action (such as exenatide and
sitagliptin), or inhibiting glucose absorption from the diet (such
as alpha glucosidase inhibitors) [Nature 2001, 414, 821-827].
[0009] Glucose is unable to diffuse across the cell membrane and
requires transport proteins. The transport of glucose into
epithelial cells is mediated by a secondary active cotransport
system, the sodium-D-glucose cotransporter (SGLT), driven by a
sodium-gradient generated by the Na+/K+-ATPase. Glucose accumulated
in the epithelial cell is further transported into the blood across
the membrane by facilitated diffusion through GLUT transporters
[Kidney International 2007, 72, S27-S35].
[0010] SGLT belongs to the sodium/glucose cotransporter family
SLCA5. Two different SGLT isoforms, SGLT1 and SGLT2, have been
identified to mediate renal tubular glucose reabsorption in humans
[Curr. Opinon in Investigational Drugs (2007): 8(4), 285-292 and
references cited herein]. Both of them are characterized by their
different substrate affinity. Although both of them show 59%
homology in their amino acid sequence, they are functionally
different. SGLT1 transports glucose as well as galactose, and is
expressed both in the kidney and in the intestine, while SGLT2 is
found exclusively in the S1 and S2 segments of the renal proximal
tubule. As a consequence, glucose filtered in the glomerulus is
reabsorbed into the renal proximal tubular epithelial cells by
SGLT2, a low-affinity/high-capacity system, residing on the surface
of epithelial cell lining in S1 and S2 tubular segments. Much
smaller amounts of glucose are recovered by SGLT1, as a
high-affinity/low-capacity system, on the more distal segment of
the proximal tubule. In healthy human, more than 99% of plasma
glucose that is filtered in the kidney glomerulus is reabsorbed,
resulting in less than 1% of the total filtered glucose being
excreted in urine. It is estimated that 90% of total renal glucose
absorption is facilitated by SGLT2; remaining 10% is likely
mediated by SGLT1 [J. Parenter. Entert Nutr. 2004, 28,
364-371].
[0011] The SGLT2 was cloned as a candidate sodium glucose
cotransporter, and its tissue distribution, substrate specificity,
and affinities are reportedly very similar to those of the
low-affinity sodium glucose co-transporter in the renal proximal
tubule. A drug with a mode of action of SGLT2 inhibition will be a
novel and complementary approach to existing classes of medication
for diabetes and its associated diseases to meet the patient's
needs for both blood glucose control, while preserving insulin
secretion. In addition, SGLT2 inhibitors which lead to loss of
excess glucose thereby excess calorie may have additional potential
for the treatment of obesity.
[0012] Indeed small molecule SGLT2 inhibitors have been discovered
and antidiabetic therapeutic potential of such molecules have been
reported in literature [T-1095 (Diabetes, 1999, 48, 1794-1800,
Dapagliflozin (Diabetes, 2008, 57, 1723-1729)]. Various O-aryl and
O-heteroaryl glycosides have been reported as SGLT-2 inhibitors in
patent publications such as: WO 01/74834, WO 03/020737, US
04/0018998, WO 01/68660, WO 01/16147, WO 04/099230, WO 05/011592,
US 06/0293252, WO 05/021566.
[0013] Various glucopyranosyl-substituted aromatic and
heteroaromatic compounds have also been reported as SGLT-2
inhibitors in patent publications such as: WO 01/27128, WO
04/080990, US 06/0025349, WO 05/085265, WO 05/085237, WO 06/054629,
WO 06/011502.
[0014] SGLT1 is predominantly found in the intestine and plays a
major role in the absorption of D-glucose and D-galactose.
Therefore, SGLT1 inhibitors have the potential to act both in the
kidney as well as the intestine to reduce calorie intake and
hyperglycemia.
[0015] WO2004/018491 discloses pyrazole derivatives which are SGLT1
inhibitors.
[0016] Glucopyranosyl-substituted aromatic or heteroaromatic
compounds where, in general, the sugar moiety has been modified at
C4, C5, or C6 positions of pyranose have been published (US
06/0009400, US 06/0019948, US 06/0035841, US 06/0074031, US
08/002,7014, WO 08/016,132).
[0017] For the purposes of this invention inhibition of SGLT means
inhibitions exclusively of SGLT2, inhibitions exclusively of SGLT1
or inhibition of both SGLT1 and SGLT2.
[0018] Thus, as a first embodiment, the invention provides a
compound of formula I:
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein Rings A and
B are independently C.sub.6-10aryl, C.sub.3-7cycloalkyl, heteroaryl
or heterocyclic; L.sub.1 is --S(O).sub.p--, --N(R.sup.3)--, or
--(CH.sub.2).sub.n--, provided that L.sub.1 is not --N(R.sup.3)--
when X is --O--; L.sub.2 is --(CH.sub.2).sub.nO(CH.sub.2).sub.m--,
--S(O).sub.p--, --N(R.sup.3)--, --Si(R')(R'')--,
--(C(R')(R'')).sub.n--, --(CH.sub.2).sub.nC(O)(CH.sub.2).sub.m--,
--(CH.sub.2).sub.nC(O)NR.sup.3(CH.sub.2).sub.m--,
--(CH.sub.2).sub.nNR.sup.3C(O)(CH.sub.2).sub.m,
--C.sub.2-6alkenyl-, --C(O)C.sub.2-6alkenyl-,
--N(R)C(O)N(R.sup.3)--, --N(R.sup.3)SO.sub.2--, or
--SO.sub.2N(R.sup.3)--; V is halogen, OR.sup.1b or hydrogen; with
the proviso that, when V is --OR.sup.1b, Y is C.sub.6-10aryl,
L.sub.1 is bond, L.sub.2 is --CH.sub.2--, rings A and B are phenyl,
then Y is not unsubstituted aryl or an aryl that is substituted
exclusively with halogen, C.sub.1-6haloalkyl,
C.sub.1-6perhaloalkyl, C.sub.1-6alkoxy, C.sub.9-6haloalkoxy,
C.sub.1-6perhaloalkoxy or cyano as substituents; t is an integer
from 1-4; m, for each occurrence, is independently, 0 or an integer
from 1-4; n, for each occurrence, is independently, 0 or an integer
from 1-4; p, for each occurrence, is independently, 0 or an integer
from 1-2; R' and R'', for each occurrence, are independently
hydrogen, halogen, C.sub.1-6alkyl, or C.sub.1-6perhaloalkyl or
taken together form a cyclic ring which may optionally have
heteroatoms selected from O, N or S; R.sup.1, R.sup.1a and R.sup.1b
are independently selected from hydrogen, C.sub.1-6alkyl,
C.sub.6-10arylC.sub.1-4alkyl, --C(O)C.sub.6-10aryl or
--C(O)C.sub.1-6alkyl; R.sup.2 and R.sup.2a, for each occurrence,
are independently halogen, hydroxy, C.sub.1-4hydroxylalkyl, cyano,
--NR.sup.4R.sup.5, --CH.sub.2NR.sup.4R.sup.5, C.sub.1-4alkyl,
C.sub.3-7cycloalkyl, C.sub.1-4alkoxy, C.sub.3-7cycloalkoxy,
--S(O).sub.pR.sup.3, --S(O).sub.2NR.sup.4R.sup.5,
--OS(O).sub.2R.sup.3, --C(O)R.sup.3, --C(O)OR.sup.3,
--CH.sub.2C(O)OR.sup.3, --C(O)NR.sup.4R.sup.5,
--CH.sub.2C(O)NR.sup.4R.sup.5, --NR.sup.3C(O)NR.sup.4R.sup.5,
--NR.sup.3C(O)OR.sup.3, C.sub.1-6 haloalkyl, C.sub.1-6
perhaloalkyl, C.sub.3-7cycloalkyl,
C.sub.3-7cyoloalkylC.sub.1-4alkyl, C.sub.6-10aryl,
C.sub.6-10arylC.sub.1-4alkyl, C.sub.8-10aryloxy, heterocyclyl,
heterocyclylC.sub.1-4alkyl, heteroaryl, heteroatylC.sub.1-4alkyl,
heteroaryloxy, or heterocycloxy; R.sup.3 is hydrogen,
C.sub.1-6alkyl, C.sub.3-7 cycloalkyl, C.sub.6-10aryl, heteroaryl,
--NR.sup.4R.sup.5 or heterocyclyl; q, for each occurrence, is
independently 0 or an integer from 1-3; Y is C.sub.6-10aryl,
C.sub.3-7cycloalkyl, heteroaryl, or heterocyclic, each of which may
be optionally substituted;
X is S(O).sub.p or O;
[0019] R.sup.4 and R.sup.5, for each occurrence, are each
independently hydrogen, C.sub.1-6alkyl, C.sub.3-7 cycloalkyl,
C.sub.3-7cycloalkylC.sub.1-4alkyl, C.sub.6-10arylC.sub.1-4alkyl,
C.sub.6-10aryl, heteroaryl, heteroarylC.sub.1-4alkyl, heterocyclyl,
or heterocyclylC.sub.1-4alkyl, or R.sup.4 and R.sup.5 taken
together may form a monocyclic or a bicyclic ring system which may
be saturated, partially saturated or aromatic and may optionally
have additional heteroatoms selected from O, N or S, the said ring
system may further be optionally substituted; R.sup.6 and R.sup.7,
for each occurrence, are independently hydrogen, C.sub.1-6alkyl,
C.sub.1-6 hydroxyalkyl, C.sub.6-10aryl,
C.sub.6-10arylC.sub.1-4alkyl, C.sub.3-7cycloalkyl, heterocyclyl,
heterocyclylC.sub.1-4alkyl, heteroaryl or heteroarylC.sub.1-4alkyl;
or R.sup.6 and R.sup.7 taken together may form a spiro, monocyclic
or a bicyclic ring system which may be saturated or partially
saturated and may optionally have additional heteroatoms selected
from O, N or S, the said ring system may further be optionally
substituted; wherein when a group is optionally substituted, the
substituents are selected from the group consisting of hydroxyl,
cyano, nitro, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, C.sub.2-6alkenyloxy, C.sub.2-6alkynyloxy, halogen,
C.sub.1-6haloalkyl, C.sub.1-6perhaloalkyl, C.sub.1-6-alkylcarbonyl,
(CH.sub.2).sub.n--COOR.sup.3, amino, C.sub.1-6-alkylamino,
di-C.sub.1-6-alkylamino, aminocarbonyl,
C.sub.1-6-alkylaminocarbonyl, di-C.sub.1-6-alkylaminocarbonyl,
C.sub.1-6-alkylcarbonylamino,
C.sub.1-6-alkylcarbonyl(C.sub.1-6-alkyl)amino,
C.sub.1-6alkoxycarbonylamino, C.sub.1-6-alkylsulfonylamino,
C.sub.1-6-alkylsulfonyl(C.sub.1-6-alkyl)amino, C.sub.1-6alkylthio,
C.sub.1-6-alkylsulfanyl, C.sub.1-6-alkylsulfinyl,
C.sub.1-6-alkylsulfonyl, aminosulfonyl,
C.sub.1-6-alkylaminosulfonyl and di-C.sub.1-6alkylaminosulfonyl,
aminocarbonylC.sub.1-6alkyl,
C.sub.1-6alkylaminocarbonylC.sub.1-6alkyl,
di-C.sub.1-6alkylaminocarbonylC.sub.1-6alkyl,
sulfanylC.sub.1-6alkyl, C.sub.1-6alkylsulfanylC.sub.1-6alkyl,
sulfinylC.sub.1-6alkyl, C.sub.1-6alkylsulfinylC.sub.1-6alkyl,
sulfonylC.sub.1-6alkyl, C.sub.1-6alkylsulfonylC.sub.1-6alkyl,
cycloalkyl, C.sub.6-10aryl (such as a phenyl), heterocyclyl,
heteroaryl, heterocyclylcarbonyl, pyrrolidinocarbonyl,
azetidinocarbonyl, cycloalkylcarbonylamino,
cyclopropylcarbonylamino, cyclopentycarbonylamino,
cyclohexylcarbonylamino, C.sub.6-10arylcarbonylamino, and
phenylcarbonylamino, wherein each of the aforementioned groups may
be optionally substituted by one or more halogen, C.sub.1-6alkyl,
hydroxyl, oxo, C.sub.1-6-alkoxy, amino, C.sub.1-6-alkylamino,
di-C.sub.1-6-alkylamino or cyano.
[0020] For purposes of interpreting this specification, the
following definitions will apply and whenever appropriate, terms
used in the singular will also include the plural and vice
versa.
[0021] As used herein, the term "alkyl" refers to a fully saturated
branched or unbranched hydrocarbon moiety. Preferably the alkyl
comprises 1 to 20 carbon atoms, more preferably 1 to 16 carbon
atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon
atoms. Representative examples of alkyl include, but are not
limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl,
sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl,
n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl,
n-heptyl, n-octyl, n-nonyl, or n-decyl.
[0022] "Alkylene" refers to a straight or branched divalent
hydrocarbon chain consisting solely of carbon and hydrogen atoms,
having from one to twelve carbon atoms, preferably one to 6 carbon
atoms, and linking the rest of the molecule to a radical group.
Examples of alkylene groups include methylene, ethylene, propylene,
n-butylene, and the like. The alkylene is attached to the rest of
the molecule through a single bond and to the radical group through
a single bond. The points of attachment of the alkylene to the rest
of the molecule and to the radical group can be through one carbon
or any two carbons within the chain. In one embodiment, an alkylene
group may be optionally substituted by one or more of the following
groups: C.sub.1-4 alkyl, trihaloC.sub.1-4alkyl, halogen, or
hydroxyl.
[0023] As used herein, the term "haloalkyl" refers to an alkyl, as
defined herein, that is substituted by one or more halo groups as
defined herein. Preferably the haloalkyl can be monohaloalkyl,
dihaloalkyl or polyhaloalkyl including perhaloalkyl. A
monohaloalkyl can have one iodo, bromo, chloro or fluoro
substituent. Dihaloalky and polyhaloalkyl groups can be substituted
with two or more of the same halo atoms or a combination of
different halo groups. Preferably, a polyhaloalkyl is substituted
with up to 12, 10, 8, 6, 4, 3, or 2 halo groups. Non-limiting
examples of haloalkyl include fluoromethyl, difluoromethyl,
trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,
pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,
dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl
and dichloropropyl. A perhaloalkyl refers to an alkyl having all
hydrogen atoms replaced with halo atoms.
[0024] "Halogen" or "halo" may be fluoro, chloro, bromo or
iodo.
[0025] As used herein, the term "hydroxyalkyl" refers to an alkyl,
as defined herein, that is substituted by one or more hydroxy
groups. Preferably the hydroxyalkyl can be monohydroxyalkyl or
dihydroxyalkyl. Non-limiting examples of hydroxyalkyl include
2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and the like.
[0026] The term "alkenyl" refers to a monovalent hydrocarbon having
at least one carbon-carbon double bond. The term
"C.sub.2-C.sub.6alkenyl" refers to a monovalent hydrocarbon having
two to six carbon atoms and comprising at least one carbon-carbon
double bond.
[0027] The term "alkynyl" refers to a monovalent hydrocarbon having
at least one carbon-carbon triple bond. The term
"C.sub.2-C.sub.6-alkynyl" refers to a monovalent hydrocarbon having
two to six carbon atoms and comprising at least one carbon-carbon
triple bond.
[0028] As used herein, the term "alkoxy" refers to alkyl-O--,
wherein alkyl is defined herein above. Representative examples of
alkoxy include, but are not limited to, methoxy, ethoxy, propoxy,
2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy,
cyclopropyloxy-, cyclohexyloxy- and the like. Preferably, alkoxy
groups have about 1-6, more preferably about 1-4 carbons.
[0029] As used herein, the term "haloalkoxy" refers to
haloalkyl-O--, wherein haloalkyl is defined herein above. A
representative example of a haloalkoxy is 1,2-dichloroethoxy.
Preferably, haloalkoxy groups have about 1-6, more preferably about
1-4 carbons.
[0030] As used herein, the term "perhaloalkoxy" refers to
perhaloalkyl-O--, wherein perhaloalkyl is defined herein above. A
representative example of a haloalkoxy is trifluoromethoxy.
Preferably, perhaloalkoxy groups have about 1-6, more preferably
about 1-4 carbons.
[0031] Alkyl, alkenyl, alkynyl, and alkoxy groups, containing the
requisite number of carbon atoms, can be unbranched or branched.
The requisite number of carbon may be represented as C.sub.1-6,
C.sub.1-4, etc.
[0032] The term "aryl" refers to monocyclic or bicyclic aromatic
hydrocarbon groups having 6-10 carbon atoms in the ring portion.
Non-limiting examples include phenyl and naphthyl, each of which
may optionally be substituted by 1-4 substituents, such as
C.sub.1-6alkyl, trifluoromethyl, C.sub.3-7cycloalkyl, halogen,
hydroxy, C.sub.1-6alkoxy, acyl, C.sub.1-6alkyl-C(O)--O--,
C.sub.6-10aryl-O--, heteroaryl-O--, amino, thiol,
C.sub.1-6alkyl-S--, C.sub.6-10aryl-S--, nitro, cyano, carboxy,
C.sub.1-6alkyl-O--C(O)--, carbamoyl, C.sub.1-6alkyl-S(O)--,
sulfonyl, sulfonamido, or heterocyclyl.
[0033] The term "aryl" also refers to a bicyclic group in which a
monocyclic aryl ring is fused to one or more or heterocyclyl rings
or cycloalkyl rings, where the radical or point of attachment is on
the aryl ring. Nonlimiting examples include tetrahydronaphthylene,
indane, benzoxazine, and chroman.
[0034] As used herein, the term "acyl" refers to a group R--C(O)--,
wherein R in the acyl residue is C.sub.1-6alkyl, or
C.sub.1-6alkoxy, or C.sub.6-10aryl, or heteroaryl. Also preferably,
one or more carbons in the acyl residue may be replaced by
nitrogen, oxygen or sulfur as long as the point of attachment to
the parent remains at the carbonyl. Examples of acyl include but
are not limited to, acetyl, benzoyl, propionyl, isobutyryl,
t-butoxycarbonyl, benzyloxycarbonyl and the like. Lower acyl refers
to acyl containing one to four carbons.
[0035] As used herein, the term "carbamoyl" refers to
H.sub.2NC(O)--, C.sub.1-6alkyl-NHC(O)--,
(C.sub.1-6alkyl).sub.2NC(O)--, C.sub.6-10aryl-NHC(O)--,
C.sub.1-6alkyl(C.sub.6-10aryl)-NC(O)--, heteroaryl-NHC(O)--,
C.sub.1-6alkyl(heteroaryl)-NC(O)--,
C.sub.6-10aryl-C.sub.1-6alkyl-NHC(O)--, or
C.sub.1-6alkyl(C.sub.6-10aryl-C.sub.1-6alkyl)-NC(O)--.
[0036] As used herein, the term "sulfonyl" refers to R--SO.sub.2--,
wherein R is hydrogen, C.sub.1-6alkyl, C.sub.6-10aryl, hereoaryl,
C.sub.6-10aryl-C.sub.1-6alkyl, heteroaryl-C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.6-10aryloxy, C.sub.3-7cycloalkyl, or
heterocyclyl.
[0037] As used herein, the term "sulfonamido" refers to
C.sub.1-6alkyl-S(O).sub.2--NH--, C.sub.6-10aryl-S(O).sub.2--NH--,
C.sub.6-10aryl-C.sub.1-6alkyl-S(O).sub.2--NH--,
heteroaryl-S(O).sub.2--NH--,
heteroaryl-C.sub.1-6alkyl-S(O).sub.2--NH--,
C.sub.1-6alkyl-S(O).sub.2--N(C.sub.1-6alkyl)-,
C.sub.6-10aryl-S(O).sub.2--N(C.sub.1-6alkyl)-,
C.sub.6-10aryl-C.sub.1-6alkyl-S(O).sub.2--N(C.sub.1-6alkyl)-,
heteroaryl-S(O).sub.2--N(C.sub.1-6alkyl)-, or
heteroaryl-C.sub.1-6alkyl-S(O).sub.2--N(C.sub.1-6alkyl)-.
[0038] As used herein, the term "sulfamoyl" refers to
(R).sub.2NSO.sub.2--, wherein R, for each occurrence is
independently hydrogen, C.sub.1-6alkyl, C.sub.6-10aryl, hereoaryl,
C.sub.6-10aryl-C.sub.1-6alkyl, heteroaryl-C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.6-10aryloxy, C.sub.3-7cycloalkyl, or
heterocyclyl.
[0039] As used herein, the term "heterocyclyl" or "heterocyclo"
refers to an optionally substituted, saturated or unsaturated
non-aromatic ring or ring system, e.g., which is a 4-, 5-, 6-, or
7-membered monocyclic, 7-, 8-, 9-, 10-, 11-, or 12-membered
bicyclic or 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring
system and contains at least one heteroatom selected from O, S and
N, where the N and S can also optionally be oxidized to various
oxidation states. The heterocyclic group can be attached at a
heteroatom or a carbon atom. The heterocyclyl can include fused or
bridged rings as well as spirocyclic rings. Examples of
heterocycles include dihydrofuranyl, [1,3]dioxolane, 1,4-dioxane,
1,4-dithiane, piperazinyl, 1,3-dioxolane, imidazolidinyl,
imidazolinyl, pyrrolidine, dihydropyran, oxathiolane, dithiolane,
I,3-dioxane, 1,3-dithianyl, oxathianyl, thiomorpholinyl, oxiranyl,
aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl,
tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, azepinyl,
oxapinyl, oxazepinyl and diazepinyl.
[0040] In one embodiment, a heterocyclyl may be substituted with 1,
2 or 3 substituents selected from the groups consisting of the
following: [0041] (a) C.sub.1-6alkyl; [0042] (b) hydroxy (or
protected hydroxy); [0043] (c) halo; [0044] (d) oxo, i.e., .dbd.O;
[0045] (e) amino (i.e. NH.sub.2), C.sub.1-6alkylamino or
di-(C.sub.1-6alkyl)amino; [0046] (f) C.sub.1-6alkoxy; [0047] (g)
C.sub.3-7cycloalkyl; [0048] (h) carboxyl; [0049] (i)
heterocyclooxy, wherein heterocyclooxy denotes a heterocyclic group
bonded through an oxygen bridge; [0050] (j)
C.sub.1-6alkyl-O--C(O)--; [0051] (k) mercapto; [0052] (l) nitro;
[0053] (m) cyano; [0054] (n) sulfamoyl or sulfonamido; [0055] (o)
C.sub.6-10aryl; [0056] (p) C.sub.1-6alkyl-C(O)--O--; [0057] (q)
C.sub.6-10aryl-C(O)--O--; [0058] (r) C.sub.6-10aryl-S--; [0059] (s)
C.sub.6-10aryloxy; [0060] (t) C.sub.1-6alkyl-S--; [0061] (u) formyl
i.e., HC(O)--; [0062] (v) carbamoyl; [0063] (w)
C.sub.6-10aryl-C.sub.1-6alkyl-; and [0064] (x) C.sub.6-10aryl
substituted with C.sub.1-6alkyl, C.sub.3-7cycloalkyl,
C.sub.1-6alkoxy, hydroxy, amino, C.sub.1-6alkyl-C(O)--NH--,
C.sub.1-6alkylamino, di-(C.sub.1-6alkyl)amino or halogen.
[0065] As used herein, the term "heterocyclylalkyl" is a
heterocyclyl as defined above which is attached to another moiety
through an alkylene group, e.g. morpholine-CH.sub.2--.
[0066] As used herein, the term "cycloalkyl" refers to saturated or
partially unsaturated (but not aromatic) monocyclic, bicyclic or
tricyclic hydrocarbon groups of 3-12 carbon atoms, preferably 3-9,
or 3-7 carbon atoms, each of which can be optionally substituted by
one, or two, or three, or more substituents, such as
C.sub.1-6alkyl, halo, oxo, hydroxy, C.sub.1-6alkoxy,
C.sub.1-6alkyl-C(O)--, carbamoyl, C.sub.1-6alkyl-NH--,
(C.sub.1-6alkyl).sub.2N--, thiol, C.sub.1-6alkyl-S--, nitro, cyano,
carboxy, C.sub.1-6alkyl-O--C(O)--, sulfonyl, sulfonamido,
sulfamoyl, or heterocyclyl. Exemplary monocyclic hydrocarbon groups
include, but are not limited to, cyclopropyl, cyclobutyl,
cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl. Exemplary
bicyclic hydrocarbon groups include bornyl, decahydronaphthyl,
bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,
6,6-dimethylbicyclo[3.1.1]heptyl,
2,6,6-trimethylbicyclo[3.1.1]heptyl, or bicyclo[2.2.2]octyl.
Exemplary tricyclic hydrocarbon groups include adamantyl.
[0067] As used herein, the term "aryloxy" refers to an --O-aryl,
wherein aryl is defined herein.
[0068] As used herein, the term "heteroaryloxy" refers to an
--O-heteroaryl, wherein heteroaryl is defined herein.
[0069] As used herein, the term "heteroaryl" refers to a 5-14
membered monocyclic- or bicyclic-aromatic ring system, having 1 to
8 heteroatoms selected from N, O or S. Preferably, the heteroaryl
is a 5-10 or 5-7 membered ring system. Examples of monocyclic
heteroaryl groups include pyridyl, thienyl, furanyl, pyrrolyl,
pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl.
Examples of bicyclic heteroaryl groups include indolyl,
benzofuranyl, quinolyl, isoquinolyl indazolyl, indolinyl,
isoindolyl, indolizinyl, benzamidazolyl, and quinolinyl. More
specific heteroaryl groups include 2- or 3-thien-2-yl, 2- or
3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or
5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-,
4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or
5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or
4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl,
2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl.
[0070] The term "heteroaryl" also refers to a group in which a
heteroaromatic ring is fused to one or more cycloalkyl, or
heterocyclyl rings, where the radical or point of attachment is on
the heteroaromatic ring. Nonlimiting examples include
5,6,7,8-tetrahydroquinoline and
6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine.
[0071] A heteroaryl group may be mono-, bi-, tri-, or polycyclic,
preferably mono-, bi-, or tricyclic, more preferably mono- or
bicyclic.
[0072] "Heteroaryl" and "heterocyclyl" is also intended to include
oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of tertiary
ring nitrogen.
[0073] When an alkyl, alkenyl, alkoxy, cycloalkyl, aryl, arylalkyl,
heteroaryl, heterocyclyl, heterocyclylalkyl is optionally
substituted, it may be substituted with one or more than one
substituents selected from hydroxyl, cyano, nitro, C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, C.sub.1-6-alkoxy,
C.sub.2-6-alkenyloxy, C.sub.2-6-alkynyloxy, halogen,
C.sub.1-6haloalkyl, C.sub.1-6perhaloalkyl, C.sub.1-6alkylcarbonyl,
(CH.sub.2).sub.n--COOR.sup.3, amino, C.sub.1-6-alkylamino,
di-C.sub.1-6-alkylamino, C.sub.1-6-alkylaminocarbonyl,
di-C.sub.1-6-alkylaminocarbonyl, C.sub.1-6-alkylcarbonylamino,
C.sub.1-6-alkylcarbonyl(C.sub.1-6-alkyl)amino,
C.sub.1-6-alkylsulfonylamino,
C.sub.1-6-alkylsulfonyl(C.sub.1-6-alkyl)amino,
C.sub.1-6-alkylthiol, C.sub.1-6-alkylsulfanyl,
C.sub.1-6-alkylsulfinyl, aminosulfonyl,
C.sub.1-6-alkylaminosulfonyl and di-C.sub.1-6alkylaminosulfonyl,
aminocarbonylC.sub.1-6alkyl, C.sub.1-6aminocarbonylC.sub.1-6alkyl,
di-C.sub.1-6aminocarbonylC.sub.1-6alkyl, sulfanylC.sub.1-6alkyl,
C.sub.1-6alkylsulfanylC.sub.1-6alkyl, sulfinylC.sub.1-6alkyl,
C.sub.1-6alkylsulfinylC.sub.1-6alkyl, sulfonylC.sub.1-6alkyl,
C.sub.1-6alkylsulfonylC.sub.1-6alkyl, C.sub.3-7cycloalkyl,
C.sub.6-10aryl, heterocyclyl, heteroaryl, where each of the
aforementioned hydrocarbon groups may be optionally substituted by
one or more halogen, C.sub.1-6alkyl, hydroxyl, oxo,
C.sub.1-6-alkoxy, amino, C.sub.1-6-alkylamino,
di-C.sub.1-6-alkylamino or cyano.
[0074] Throughout this specification and in the claims that follow,
unless the context requires otherwise, the word "comprise", or
variations such as "comprises" or "comprising", will be understood
to imply the inclusion of a stated integer or step or group of
integers or steps but not the exclusion of any other integer or
step or group of integers or steps.
[0075] "Prodrugs" is meant to indicate a compound that may be
converted under physiological conditions or by solvolysis to a
biologically active compound of the invention. Thus, the term
"prodrug" refers to a metabolic precursor of a compound of the
invention that is pharmaceutically acceptable. A prodrug may be
inactive when administered to a subject in need thereof, but is
converted in vivo to an active compound of the invention. Prodrugs
are typically rapidly transformed in vivo to yield the parent
compound of the invention, for example, by hydrolysis in blood or
conversion in the gut or liver. The prodrug compound often offers
advantages of solubility, tissue compatibility or delayed release
in a mammalian organism (see, Bundgard, H., Design of Prodrugs
(1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)).
[0076] A discussion of prodrugs is provided in Higuchi, T., et al.,
"Pro-drugs as Novel Delivery Systems," A. C. S. Symposium Series,
Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward
B. Roche, Anglican Pharmaceutical Association arid Pergamon Press,
1987.
[0077] "Optional" or "optionally" means that the subsequently
described event of circumstances may or may not occur, and that the
description includes instances where said event or circumstance
occurs and instances in which it does not. For example, "optionally
substituted aryl" means that the aryl radical may or may not be
substituted and that the description includes both substituted aryl
radicals and aryl radicals having no substitution.
[0078] "Pharmaceutically acceptable carrier, diluent or excipient"
includes without limitation any adjuvant, carrier, excipient,
glidant, sweetening agent, diluent, preservative, dye/colorant,
flavor enhancer, surfactant, wetting agent, dispersing agent,
suspending agent, stabilizer, isotonic agent, solvent, or
emulsifier which has been approved by the United States Food and
Drug Administration as being acceptable for use in humans or
domestic animals.
[0079] "Pharmaceutically acceptable salt" includes both acid and
base addition salts.
[0080] "Pharmaceutically acceptable acid addition salt" refers to
those salts which retain the biological effectiveness and
properties of the free bases, which are not biologically or
otherwise undesirable, and which are formed with inorganic acids
such as, but not limited to, hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid and the like, and
organic acids such as, but not limited to, acetic acid,
2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid,
aspartic acid, benzenesulfonic acid, benzoic acid,
4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,
capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic
acid, citric acid, cyclamic acid, dodecylsulfuric acid,
ethane-1,2-disulfonic acid, ethanesulfonic acid,
2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric
acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic
acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid,
glycerophosphorirc acid, glycolic acid, hippuric acid, isobutyric
acid, lactic acid, lactobionic acid, lauric acid, maleic acid,
malic acid, malonic acid, mandelic acid, methanesulfonic acid,
mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic
acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid,
orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic
acid, pyroglutamic acid, pyruvic acid, salicylic acid,
4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,
tartaric acid, thiocyanic acid, p-toluenesulfonic acid,
trifluoroacetic acid, undecylenic acid, and the like.
[0081] "Pharmaceutically acceptable base addition salt" refers to
those salts which retain the biological effectiveness and
properties of the free acids, which are not biologically or
otherwise undesirable. These salts are prepared from addition of an
inorganic base or an organic base to the free acid. Salts derived
from inorganic bases include, but are not limited to, the sodium,
potassium, lithium, ammonium, calcium, magnesium, iron, zinc,
copper, manganese, aluminum salts and the like. Preferred inorganic
salts are the ammonium, sodium, potassium, calcium, and magnesium
salts. Salts derived from organic bases include, but are not
limited to, salts of primary, secondary, and tertiary amines,
substituted amines including naturally occurring substituted
amines, cyclic amines and basic ion exchange resins, such as
ammonia, isopropylamine, trimethylamine, diethylamine,
triethylamine, tripropylamine, diethanolamine, ethanolamine,
deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol,
dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,
hydrabamine, choline, betaine, benethamine, benzathine,
ethylenediamine, glucosamine, methylglucamine, theobromine,
triethanolamine, tromethamine, purines, piperazine, piperidine,
N-ethylpiperidine, polyamine resins and the like. Particularly
preferred organic bases are isopropylamine, diethylamine,
ethanolamine, trimethylamine, dicyclohexylamine, choline and
caffeine.
[0082] Often crystallizations produce a solvate of the compound of
the invention. As used herein, the term "solvate" refers to an
aggregate that comprises one or more molecules of a compound of the
invention with one or more molecules of solvent. The solvent may be
water, in which case the solvate may be a hydrate. Alternatively,
the solvent may be an organic solvent. Thus, the compounds of the
present invention may exist as a hydrate, including a monohydrate,
dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and
the like, as well as the corresponding solvated forms. The compound
of the invention may be true solvates, while in other cases, the
compound of the invention may merely retain adventitious water or
be a mixture of water plus some adventitious solvent.
[0083] A "pharmaceutical composition" refers to a formulation of a
compound of the invention and a medium generally accepted in the
art for the delivery of the biologically active compound to
mammals, e.g., humans. Such a medium includes all pharmaceutically
acceptable carriers, diluents or excipients thereof.
[0084] As used herein, the terms "disease" and "condition" may be
used interchangeably or may be different in that the particular
malady or condition may not have a known causative agent (so that
etiology has not yet been worked out) and it is therefore not yet
recognized as a disease but only as an undesirable condition or
syndrome, wherein a more or less specific set of symptoms have been
identified by clinicians.
[0085] The compounds of the invention, or their pharmaceutically
acceptable salts may contain one or more asymmetric centers and may
thus give rise to enantiomers, diastereomers, and other
stereoisomeric forms that may be defined, in terms of absolute
stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino
acids. Unless otherwise indicated, the present invention is meant
to include all such possible isomers, as well as their racemic and
optically pure forms. Optically active (+) and (-), (R)- and (S)-,
or (D)- and (L)-isomers may be prepared using chiral synthons or
chiral reagents, or resolved using conventional techniques, such as
HPLC using a chiral column. When the compounds described herein
contain olefinic double bonds or other centers of geometric
asymmetry, and unless specified otherwise, it is intended that the
compounds include both E and Z geometric isomers. Likewise, all
tautomeric forms are also intended to be included.
[0086] A "stereoisomer" refers to a compound made up of the same
atoms bonded by the same bonds but having different
three-dimensional structures, which are not interchangeable. The
present invention contemplates various stereoisomers and mixtures
thereof and includes "enantiomers", which refers to two
stereoisomers whose molecules are nonsuperimposeable mirror images
of one another.
[0087] The present invention includes all pharmaceutically
acceptable isotopically-labeled compounds of Formula (I) wherein
one or more atoms are replaced by atoms having the same atomic
number, but an atomic mass or mass number different from the atomic
mass or mass number usually found in nature.
[0088] Examples of isotopes suitable for inclusion in the compounds
of the invention comprises isotopes of hydrogen, such as .sup.2H
and .sup.3H, carbon, such as .sup.11C, .sup.13C and .sup.14C,
chlorine, such as .sup.35Cl, fluorine, such as .sup.18F, iodine,
such as .sup.123I and .sup.125I, nitrogen, such as .sup.13N and
.sup.15N, oxygen, such as .sup.15O, .sup.17O and .sup.18O,
phosphorus, such as .sup.32P, and sulphur, such as .sup.35S.
Substitution with heavier isotopes such as deuterium, i.e. .sup.2H,
may afford certain therapeutic advantages resulting from greater
metabolic stability, for example, increased in vivo half-life or
reduced dosage requirements, and hence may be preferred in some
circumstances. Isotopically-labeled compounds of Formula (I) can
generally be prepared by conventional techniques known to those
skilled in the art or by processes analogous to those described in
the accompanying Examples and Preparations Sections using an
appropriate isotopically-labeled reagent in place of the
non-labeled reagent previously employed.
[0089] Various embodiments of the invention are described below. It
will be appreciated that the features specified in each embodiment
may be combined with other specified features, to provide further
embodiments.
[0090] In further or alternative embodiment of the present
invention, compounds may be represented by formula (II) or
(III)
##STR00003##
or a pharmaceutically acceptable salt thereof, wherein, [0091]
R.sup.2 and R.sup.2a, for each occurrence, are independently
selected from halogen, hydroxy, C.sub.1-4 hydroxylalkyl, cyano,
--NR.sup.4R.sup.5, --CH.sub.2NR.sup.4R.sup.5, C.sub.1-4 alkyl,
C.sub.3-7 cycloalkyl, C.sub.1-4 alkoxy, --S(O).sub.pR.sup.3,
--OS(O).sub.pR.sup.3, --C(O)R.sup.3, --C(O)OR.sup.3,
--CH.sub.2C(O)OR.sup.3, --C(O)NR.sup.4R.sup.5,
--CH.sub.2C(O)NR.sup.4R.sup.5, --NR.sup.3C(O)NR.sup.4R.sup.5,
--NR.sup.3C(O)OR.sup.3, C.sub.1-6 haloalkyl, C.sub.1-6
perhaloalkyl, C.sub.6-10aryloxy, heterocyclyl and heteroaryl;
[0092] p, for each occurrence, is independently 0, 1 or 2; [0093]
q, for each occurrence, is independently 1, 2, or 3; and [0094] Y
is optionally substituted C.sub.6-10aryl or an optionally
substituted heteroaryl.
[0095] In further or alternative embodiment of the present
invention, compounds may be represented by formula (IV) or (V)
##STR00004##
or a pharmaceutically acceptable salt thereof, wherein, [0096]
R.sup.2 and R.sup.2a, for each occurrence, are independently
selected from halogen, hydroxy, C.sub.1-4 hydroxylalkyl, cyano,
--NR.sup.4R.sup.5, --CH.sub.2NR.sup.4R.sup.5, C.sub.1-4 alkyl,
C.sub.3-7 cycloalkyl, C.sub.1-4 alkoxy, --S(O).sub.pR.sup.3,
--OS(O).sub.pR.sup.3, --C(O)R.sup.3, --C(O)OR.sup.3,
--CH.sub.2C(O)OR.sup.3, --C(O)NR.sup.4R.sup.5,
--CH.sub.2C(O)NR.sup.4R.sup.5, --NR.sup.3C(O)NR.sup.4R.sup.5,
--NR.sup.3C(O)OR.sup.3, C.sub.1-6 haloalkyl, C.sub.1-6
perhaloalkyl, C.sub.6-10aryloxy, heterocyclyl and heteroaryl;
[0097] p, for each occurrence, is independently 0, 1 or 2; [0098]
q, for each occurrence, is independently 1, 2, or 3; and [0099] Y
is optionally substituted C.sub.6-10aryl or an optionally
substituted heteroaryl.
[0100] References hereinafter to compounds of formula (I) apply
equally to compounds of formula (II), (III), (IV) and (V).
[0101] References hereinafter to embodiments of the invention apply
equally to compounds of formula (I) and compounds of formula (II),
(III), (IV) and (V), insofar as the embodiments are present.
[0102] Various embodiments of the invention are described below. It
will be appreciated that the feature specified in each embodiment
may be combined with other specified features, to provide further
embodiments.
[0103] In one embodiment, rings A and B are phenyl.
[0104] In another embodiment, X is O.
[0105] In another embodiment, X is S(O).sub.p.
[0106] In another embodiment, R.sup.6 and R.sup.7 taken together
can form a cyclic ring, which may optionally have heteroatoms
selected from O, N or S, Non limitative examples of such spiro
cyclic systems are
##STR00005##
[0107] In another embodiment, L.sub.1 is a bond.
[0108] In another embodiment, L.sub.2 is --(CH.sub.2)--.
[0109] In another embodiment, V is halogen, e.g. fluoro. In a
further embodiment, V is --OH.
[0110] In another embodiment, R.sup.1 and R.sup.1a are
hydrogen.
[0111] In another embodiment, R.sup.2 is halogen, e.g. chloro.
[0112] In another embodiment, R.sup.2a is C.sub.1 alkoxy, e.g.
methoxy or ethoxy.
[0113] In another embodiment, q=1.
[0114] In another embodiment, rings A and B are phenyl, L1 is a
bond, L2 is --(CH.sub.2)--, V is --OH, R.sup.1 and R.sup.1a are
hydrogen, R.sup.2 is chloro, R.sup.2a is ethoxy and q=1.
[0115] In another embodiment of the invention, Y is C.sub.6-10aryl
or heteroaryl.
[0116] In another embodiment of the invention, Y is a substituted
phenyl group.
[0117] In another embodiment of the invention, Y is
##STR00006## [0118] R.sup.10 is independently halogen, hydroxy,
C.sub.1-4 hydroxylalkyl, cyano, --NR.sup.16R.sup.17, oxo (.dbd.O),
--CH.sub.2NR.sup.16R.sup.17, C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl,
C.sub.1-4alkoxy, --S(O).sub.pR.sup.18, --OS(O).sub.2R.sup.18,
--C(O)R.sup.18, --C(O)OR.sup.18, --CH.sub.2C(O)OR.sup.18,
--C(O)NR.sup.16R.sup.17, --CH.sub.2C(O)NR.sup.16R.sup.17,
--NR.sup.18C(O)NR.sup.16R.sup.17, --NR.sup.18C(O)R.sup.18,
--NR.sup.18C(O)OR.sup.18, --CH.sub.2NR.sup.16C(O)OR.sup.18,
--CH.sub.2NR.sup.16C(O)NR.sup.16R.sup.17,
--CH.sub.2NR.sup.16S(O).sub.pR.sup.18,
--S(O).sub.2NR.sup.16R.sup.17, C.sub.1-6 haloalkyl, C.sub.1-6
perhaloalkyl, C.sub.6-10aryloxy, heterocyclyl, heteroaryl; [0119]
R.sup.18 is hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl,
C.sub.6-10aryl, heteroaryl, or heterocyclyl; [0120] R.sup.16 and
R.sup.17 are independently hydrogen, C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl, C.sub.6-10aryl(C.sub.1-4)alkyl, C.sub.6-10aryl,
heteroaryl, heteroaryl(C.sub.1-4)alkyl, heterocyclyl,
heterocyclyl(C.sub.1-4alkyl or [0121] R.sup.16 and R.sup.17 taken
together may form a monocyclic or a bicyclic ring system which may
be saturated, partially saturated or aromatic and may optionally
have additional heteroatoms selected from O, N or S, the said ring
system may further be optionally substituted; p, for each
occurrence, is independently 0, 1 or 2; and w is 0, or an integer
from 1-4.
[0122] In another embodiment, R.sup.10 is halogen, e.g. fluoro,
chloro or bromo, hydroxyl, C.sub.1-4 hydroxylalkyl, e.g.
hydroxymethyl or 2-hydroxyethyl, cyano, --CN, --NR.sup.16R.sup.17,
e.g. methylamino or dimethylamino, --CH.sub.2NR.sup.16R.sup.17,
e.g. methylaminomethyl, --CH.sub.2NR.sup.18C(O)R.sup.18, e.g.
CH.sub.2NHC(O)CH.sub.3, CH.sub.2NR.sup.16C(O)OR.sup.18, e.g.
--CH.sub.2NHC(O).sub.2CH.sub.3,
CH.sub.2NR.sup.16C(O)NR.sup.16R.sup.17, e.g.
--CH.sub.2NHC(O)NHCH.sub.3, CH.sub.2NR.sup.16S(O).sub.pR.sup.18,
e.g. --CH.sub.2NHS(O).sub.2CH.sub.3, --S(O).sub.2NR.sup.16R.sup.17,
e.g. --S(O).sub.2NHCH.sub.3, heterocyclyl, e.g. piperidinyl,
morpholinyl, piperazinyl, or heteroaryl, e.g. pyrimidine, pyrazole,
pyrrole, thiophene, imidazole, tetrazole, triazole, pyridine, and
pyrazine, and w is 1-3.
[0123] Another embodiment of the invention is where Y is
##STR00007## ##STR00008##
[0124] Another embodiment of the invention is where Y is
##STR00009## ##STR00010##
[0125] Another embodiment of the invention is where Y is
##STR00011## ##STR00012##
[0126] Another embodiment of the invention is where Y is
##STR00013##
[0127] A specific embodiment of the compounds of formulae (I),
(II), (III), (IV) or (V) is selected from: [0128]
(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxybenzyl)-phenyl]-3,4,5-trihydr-
oxy tetrahydropyran-2-ylmethylsulfanyl}phenyl)acetic acid methyl
ester; [0129]
(4-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxybenzyl)phenyl]-3,4,5-t-
rihydroxytetrahydro-pyran-2-ylmethylsulfanyl}phenyl)-acetic acid;
[0130]
(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-3,4,5-tri
hydroxytetrahydropyran-2-ylmethylsulfanyl}phenyl)acetic acid
carboxamide; [0131]
2-(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4-
,5-trihydroxy-tetrahydropyran-2-ylmethylsulfanyl}phenyl)-N-methylacetamide-
; [0132]
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-6-[4-(2-hy-
droxyethyl)-phenylsulfanylmethyl]tetrahydropyran-3,4,5-triol;
[0133]
(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethanesulfonyl}-phenyl)-acetic acid
methyl ester; [0134]
(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethanesulfonyl}-phenyl)-acetic acid;
[0135]
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-6-(pyrimidin-2-yls-
ulfanylmethyl) tetrahydropyran-3,4,5-triol; [0136]
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-6-(thiazol-2-ylsul-
fanylmethyl)tetrahydropyran-3,4,5-triol; [0137]
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-6-(1-methyl-1H-tet-
razol-5-ylsulfanylmethyl)tetrahydropyran-3,4,5-triol: [0138]
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxybenzyl)-phenyl]-6-(thiophen-2-yls-
ulfanylmethyl)tetrahydropyran-3,4,5-triol; and [0139]
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-6-(5-methyl-1,1-di-
oxo-1H-1lambda*6*-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-tetrahydro-pyran-3-
,4,5-triol; [0140]
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-(4-phenyl-thio-
zol-2-ylsulfanylmethyl)-tetrahydro-pyran-3,4,5-triol; [0141]
(2S,3S,4R,5R,6S)-2-(Benzothiazol-2-ylsulfanylmethyl)-6-[4-chloro-3-(4-eth-
oxy-benzyl)-phenyl]-tetrahydro-pyran-3,4,5-triol; [0142]
(2S,3S,4R,5R,6S)-2-(1H-Benzoimidazol-2-ylsulfanyl
methyl)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3,4,5-tr-
iol; [0143]
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-(5-trifluorome-
thyl-pyridin-2-ylsulfanylmethyl)-tetrahydro-pyran-3,4,5-triol;
[0144]
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-(pyrimidin-2-y-
lsulfonylmethyl)-tetrahydro-pyran-3,4,5-triol; [0145]
4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-benzoic acid ethyl ester;
[0146]
4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-benzoic acid; [0147]
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-(4-hydroxymeth-
yl-phenylsulfanylmethyl)-tetrahydro-pyran-3,4,5-triol; [0148]
6-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-nicotinic acid; [0149]
2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-benzoic acid; [0150]
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-(2-hydroxymeth-
yl-phenylsulfanylmethyl)-tetrahydro-pyran-3,4,5-triol; [0151]
2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-benzamide; [0152]
N-(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-4-fluoro-phenyl)-acetamide;
[0153]
3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5--
trihydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-4-fluoro-benzamide;
[0154]
3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-4-fluoro-N-methyl-benzamide;
[0155]
(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-
-trihydroxy-tetrahydro-pyran-2-ylmethanesulfinyl}-phenyl)-acetic
acid; [0156]
(2S,3S,4R,5R,6S)-2-(2-Amino-phenylsulfanylmethyl)-6-[4-chloro-3-(4-
-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3,4,5-triol; [0157]
(2S,3S,4R,5R,6S)-2-(3-Amino-phenylsulfanylmethyl)-6-[4-chloro-3-(4-ethoxy-
-benzyl)-phenyl]-tetrahydro-pyran-3,4,5-triol; [0158]
(2S,3S,4R,5R,6S)-2-(4-Amino-phenylsulfanylmethyl)-6-[4-chloro-3-(4-ethoxy-
-benzyl)-phenyl]-tetrahydro-pyran-3,4,5-triol; [0159]
(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-acetic acid;
[0160]
(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-acetic acid;
[0161]
2-(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-acetamide;
[0162]
2-(3-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethanesulfonyl}-phenyl)-acetamide;
[0163]
(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-4-fluoro-phenyl)-pyrrolidin-1-yl-
-methanone; [0164]
Azetidin-1-yl-(3-{(2S,3S,4R,5R,63)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl-
]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-4-fluoro-phenyl)-m-
ethanone; [0165]
2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5
trihydroxytetrahydro-pyran-2 ylmethylsulfanyl}-N-methyl benzamide;
[0166]
2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-N-ethyl-benzamide; [0167]
3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-N-methyl-benzamide; [0168]
3-{(2S,3S,4R,5R,6S)-6-[4Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydro-
xy-tetrahydro-pyran-2-ylmethylsulfanyl}-N-ethyl-benzamide; [0169]
4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran2ylmethylsulfanyl}-N-methyl-benzamide; [0170]
4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran2ylmethylsulfanyl}-N-ethyl-benzamide; [0171]
4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran2ylmethylsulfanyl}-N-ethyl-benzamide; [0172]
(2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-pyrrolidin-1
yl-methanone; [0173]
3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-N-isopropyl-benzamide;
[0174]
(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-pyrrolidin-1
yl-methanone; [0175]
4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-N-isopropyl-benzamide;
[0176]
(4-{(2S,3S,4R,5R,6S)-6-[4Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-pyrrolidin-1
yl-methanone; [0177]
3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-N,N-dimethyl-benzamide;
[0178]
4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)phenyl]-3,4,5-trihydro-
xy-tetrahydro-pyran-2-ylmethylsulfanyl}-N,N-dimethyl-benzamide;
[0179]
2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-N,N-dimethyl-benzamide;
[0180]
4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-benzamide; [0181]
Cyclopentanecarboxylic acid
(3-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-amide; [0182]
N-(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-benzamide;
[0183] Cyclohexanecarboxylic acid
(3-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2ylmethylsulfanyl}-phenyl)-amide; [0184]
N-(2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-benzamide;
[0185]
N-(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-benzamide;
[0186] Cyclohexanecarboxylic acid
(4-{(2S,3S,4R,5R,6S)-6-[4-chloro3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-amide; [0187]
Cyclopentanecarboxylic acid
(4-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxybenzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-amide; [0188]
N-(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-acetamide;
[0189]
N-(2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-acetamide;
[0190] Cyclohexanecarboxylic acid
(2-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-amide; [0191]
Cyclopentanecarboxylic acid
(2-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-amide; [0192]
Cyclopropanecarboxylic acid
(2-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-amide; [0193]
Cyclopropanecarboxylic acid
(3-{(2S,3,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-amide; [0194]
N-(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-propionamide;
[0195]
(2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-carbamic acid
methyl ester; [0196]
(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-carbamic acid
methyl ester; [0197]
N-(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-propionamide;
[0198]
(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-carbamicacid
methyl ester; [0199]
N-(2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-propionamide;
Cyclopropanecarboxylic acid
(4-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-amide; [0200]
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-[4-(2-hydroxy
ethyl)benzenesulfonylmethyl]-tetrahydro-pyran-3,4,5-triol; [0201]
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-[3-(2-hydroxy--
ethyl)benzenesulfonylmethy]-tetrahydro-pyran-3,4,5-triol; [0202]
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-[3-(2-hydroxy--
ethyl)phenylsulfanylmethyl]-tetrahydro-pyran-3,4,5-triol; [0203]
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-(3-hydroxymeth-
yl-phenylsulfanylmethyl)-tetrahydro-pyran-3,4,5-triol; [0204]
3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-benzamide; [0205]
3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethanesulfonyl}-benzamide; [0206]
N-(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-acetamide;
[0207]
N-(3-{(2R,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethoxy}-phenyl)-acetamide; [0208]
3-{(2R,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethoxy}-benzamide; [0209]
3-{(2R,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethoxy}-N-methyl-benzamide; [0210]
(3-{(2R,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethoxy}-phenyl)-pyrrolidin-1-yl-methanone;
[0211]
Azetidin-1-yl-(3-{(2R,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-
-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethoxy}-phenyl)-methanone;
[0212]
4-{(2R,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5--
trihydroxy-tetrahydro-pyran-2-ylmethoxy}-benzamide; and
pharmaceutically acceptable salts thereof.
[0213] A specific embodiment of the compounds of formulae (I),
(II), or (III) is selected from: [0214]
(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxybenzyl)-phenyl]-3,4,5-trihydr-
oxy tetrahydropyran-2-ylmethylsulfanyl}phenyl)acetic acid methyl
ester; [0215]
(4-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxybenzyl)phenyl]-3,4,5-t-
rihydroxytetrahydro-pyran-2-ylmethylsulfanyl}phenyl)-acetic acid;
[0216]
(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-3,4,5-tri
hydroxytetrahydropyran-2-ylmethylsulfanyl}phenyl)acetic acid
carboxamide; [0217]
2-(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4-
,5-trihydroxy-tetrahydropyran-2-ylmethylsulfanyl}phenyl)-N-methylacetamide-
; [0218]
(2S,3R,4R,5R,6S)-2-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-6-[4-(2-hy-
droxyethyl)-phenylsulfanylmethyl]tetrahydropyran-3,4,5-triol;
[0219]
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-6-(pyrimidin-2-yls-
ulfanylmethyl)tetrahydropyran-3,4,5-triol;
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-6-(thiazol-2-ylsul-
fanylmethyl)tetrahydropyran-3,4,5-triol; [0220]
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-6-(1-methyl-1H-tet-
razol-5-ylsulfanylmethyl)tetrahydropyran-3,4,5-triol: [0221]
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxybenzyl)-phenyl]-6-(thiophen-2-yls-
ulfanylmethyl)tetrahydropyran-3,4,5-triol; and [0222]
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-6-(5-methyl-1,1-di-
oxo-1H-1lambda*6*-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-tetrahydro-pyran-3-
,4,5-triol; [0223]
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-(4-phenyl-thio-
zol-2-ylsulfanylmethyl)-tetrahydro-pyran-3,4,5-triol; [0224]
(2S,3S,4R,5R,6S)-2-(Benzothiazol-2-ylsulfanylmethyl)-6-[4-chloro-3-(4-eth-
oxy-benzyl)-phenyl]-tetrahydro-pyran-3,4,5-triol; [0225]
(2S,3S,4R,5R,6S)-2-(1H-Benzoimidazol-2-ylsulfanylmethyl)-6-[4-chloro-3-(4-
-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3,4,5-triol; [0226]
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-(5-trifluorome-
thyl-pyridin-2-ylsulfanylmethyl)-tetrahydro-pyran-3,4,5-triol;
[0227]
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-(pyrimidin-2-y-
lsulfonylmethyl)-tetrahydro-pyran-3,4,5-triol; [0228]
4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-benzoic acid ethyl ester;
[0229]
4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-benzoic acid; [0230]
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-(4-hydroxymeth-
yl-phenylsulfanylmethyl)-tetrahydro-pyran-3,4,5-triol; [0231]
6-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-nicotinic acid; [0232]
2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-benzoic acid; [0233]
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-(2-hydroxymeth-
yl-phenylsulfanylmethyl)-tetrahydro-pyran-3,4,5-trial; [0234]
2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-benzamide; [0235]
N-(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-4-fluoro-phenyl)-acetamide;
[0236]
3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5--
trihydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-4-fluoro-benzamide;
[0237]
3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-4-fluoro-N-methyl-benzamide;
[0238]
(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-
-trihydroxy-tetrahydro-pyran-2-ylmethanesulfinyl}-phenyl)-acetic
acid; [0239]
(2S,3S,4R,5R,6S)-2-(2-Amino-phenylsulfanylmethyl)-6-[4-chloro-3-(4-
-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3,4,5-triol; [0240]
(2S,3S,4R,5R,6S)-2-(3-Amino-phenylsulfanylmethyl)-6-[4-chloro-3-(4-ethoxy-
-benzyl)-phenyl]-tetrahydro-pyran-3,4,5-triol; [0241]
(2S,3S,4R,5R,6S)-2-(4-Amino-phenylsulfanylmethyl)-6-[4-chloro-3-(4-ethoxy-
-benzyl)-phenyl]-tetrahydro-pyran-3,4,5-triol; [0242]
(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-acetic acid;
[0243]
(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-acetic acid;
[0244]
2-(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-acetamide;
[0245]
2-(3-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethanesulfonyl}-phenyl)-acetamide;
[0246]
(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-4-fluoro-phenyl)-pyrrolidin-1-yl-
-methanone; [0247]
Azetidin-1-yl-(3-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl-
]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-4-fluoro-phenyl)-m-
ethanone; [0248]
2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5
trihydroxytetrahydro-pyran-2 ylmethylsulfanyl}-N-methyl benzamide;
[0249]
2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-N-ethyl-benzamide; [0250]
3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-N-methyl-benzamide; [0251]
3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-N-ethyl-benzamide; [0252]
4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran2ylmethylsulfanyl}-N-methyl-benzamide; [0253]
4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran2ylmethylsulfanyl}-N-ethyl-benzamide; [0254]
4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran2ylmethylsulfanyl}-N-ethyl-benzamide; [0255]
(2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-pyrrolidin-1-yl-methanon-
e; [0256]
3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,-
5-trihydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-N-isopropyl-benzamide;
[0257]
(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-
-trihydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-pyrrolidin-1-yl-m-
ethanone; [0258]
4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-N-isopropyl-benzamide;
[0259]
(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-pyrrolidin-1-yl-methanon-
e; [0260]
3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,-
5-trihydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-N,N-dimethyl-benzamide;
[0261]
4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)phenyl]-3,4,5-t-
rihydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-N,N-dimethyl-benzamide;
[0262]
2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5--
trihydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-N,N-dimethyl-benzamide;
[0263]
4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5--
trihydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-benzamide; [0264]
Cyclopentanecarboxylic acid
(3-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-amide; [0265]
N-(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-benzamide;
[0266] Cyclohexanecarboxylic acid
(3-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2ylmethylsulfanyl}-phenyl)-amide; [0267]
N-(2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-benzamide;
[0268]
N-(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-benzamide;
[0269] Cyclohexanecarboxylic acid
(4-{(2S,3S,4R,5R,6S)-6-[4-chloro3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-amide; [0270]
Cyclopentanecarboxylic acid
(4-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxybenzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-amide; [0271]
N-(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-acetamide;
[0272]
N-(2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-acetamide;
[0273] Cyclohexanecarboxylic acid
(2-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-amide; [0274]
Cyclopentanecarboxylic acid
(2-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-amide; [0275]
Cyclopropanecarboxylic acid
(2-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-amide; [0276]
Cyclopropanecarboxylic acid
(3-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-amide; [0277]
N-(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-propionamide;
[0278]
(2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-carbamic acid
methyl ester; [0279]
(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-carbamic acid
methyl ester; [0280]
N-(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-propionamide;
[0281]
(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-carbamicacid
methyl ester; [0282]
N-(2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-propionamide;
[0283] Cyclopropanecarboxylic acid
(4-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-amide; [0284]
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-[4-(2-hydroxy
ethyl)benzenesulfonylmethyl]-tetrahydro-pyran-3,4,5-triol; [0285]
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-[3-(2-hydroxy--
ethyl)benzenesulfonylmethyl]-tetrahydro-pyran-3,4,5-triol; [0286]
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-[3-(2-hydroxy--
ethyl)phenylsulfanylmethyl]-tetrahydro-pyran-3,4,5-triol; [0287]
(2S,3R,4R,5S,68)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-(3-hydroxymeth-
yl-phenylsulfanylmethyl)-tetrahydro-pyran-3,4,5-triol; [0288]
3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-benzamide; [0289]
3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethanesulfonyl}-benzamide; [0290]
N-(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-acetamide; and
pharmaceutically acceptable salts thereof.
[0291] A specific embodiment of the compounds of formulae (I), (IV)
or (V) is selected from: [0292]
N-(3-{(2R,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethoxy}-phenyl)-acetamide; [0293]
3-{(2R,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethoxy}-benzamide; [0294]
3-{(2R,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethoxy}-N-methyl-benzamide; [0295]
(3-{(2R,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethoxy}-phenyl)-pyrrolidin-1-yl-methanone;
[0296]
Azetidin-1-yl-(3-{(2R,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-
-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethoxy}-phenyl)-methanone;
[0297]
4-{(2R,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5--
trihydroxy-tetrahydro-pyran-2-ylmethoxy}-benzamide; and
pharmaceutically acceptable salts thereof.
[0298] In still another embodiment of the present invention, the
compound forms a pharmaceutically acceptable salt, selected from a
group comprising acid addition salts and base addition salts.
[0299] In still another embodiment of the present invention, the
compound is a stereoisomer or a tautomer.
[0300] The compounds of the present invention are useful as both
prophylactic and therapeutic treatments for diseases or conditions
related to the inhibition of SGLT-2 and SGLT-1.
[0301] Thus, as a further aspect, the invention relates to a method
for treating a disease or condition related to the inhibition of
SGLT-2, comprising administration of an effective therapeutic
amount of a compound of formula (I) or a pharmaceutically
acceptable salt thereof.
[0302] Compounds of formula (I) may be useful in the treatment of
metabolic disorders, or conditions such as (such as e.g.
retinopathy, nephropathy or neuropathies, diabetic foot, ulcers,
macroangiopathies), metabolic acidosis or ketosis, reactive
hypoglycaemia, hyperinsulinaemia, glucose metabolic disorder,
insulin resistance, metabolic syndrome, dyslipidaemias of different
origins, atherosclerosis and related diseases, obesity, high blood
pressure, chronic heart failure, edema and hyperuricaemia.
[0303] Compounds of formula (I) may be also suitable for preventing
beta-cell degeneration such as apoptosis or necrosis of pancreatic
beta cells, for improving or restoring the functionality of
pancreatic cells, increasing the number and size of pancreatic beta
cells, for use as diuretics or antihypertensives and for the
prevention and treatment of acute renal failure.
[0304] As a further aspect, the invention relates to a method for
treating a disorder selected from type 1 and type 2 diabetes
mellitus, complications of diabetes, comprising administration of
an effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof.
[0305] A compound of formula (I) of the present invention may be
usefully combined with another pharmacologically active compound,
or with two or more other pharmacologically active compounds, for
use in therapy. For example, a compound of the formula (I), or a
pharmaceutically acceptable salt thereof, as defined above, may be
administered simultaneously, sequentially or separately in
combination with one or more agents for the treatment of disorders
previously listed.
[0306] Therapeutic agents which are suitable for such a combination
include, for example, antidiabetic agents such as metformin,
sulphonylureas (e.g. glibenclamide, tolbutamide, glimepiride),
nateglinide, repaglinide, thiazolidinediones (e.g. rosiglitazone,
pioglitazone), PPAR-gamma-agonists (e.g. GI 262570) and
antagonists, PPAR-gamma/alpha modulators (e.g. KRP 297),
alpha-glucosidase inhibitors (e.g. acarbose, voglibose), DPPIV
inhibitors (e.g. LAF237, MK-431), alpha2-antagonists, insulin and
insulin analogues, GLP-1 and GLP-1 analogues (e.g. exendin-4) or
amylin. The list also includes inhibitors of protein
tyrosinephosphatase 1, substances that affect deregulated glucose
production in the liver, such as e.g. inhibitors of
glucose-6-phosphatase, orfructose-1,6-bisphosphatase, glycogen
phosphorylase, glucagon receptor antagonists and inhibitors of
phosphoenol pyruvate carboxykinase, glycogen synthase kinase or
pyruvate dehydrokinase, lipid lowering agents such as for example
HMG-CoA-reductase inhibitors (e.g. simvastatin, atorvastatin),
fibrates (e.g. bezafibrate, fenofibrate), nicotinic acid and the
derivatives thereof, PPAR-alpha agonists, PPAR-delta agonists, ACAT
inhibitors (e.g. avasimibe) or cholesterol absorption inhibitors
such as, for example, ezetimibe, bile acid-binding substances such
as, for example, cholestyramine, inhibitors of ileac bile acid
transport, HDL-raising compounds such as CETP inhibitors or ABC1
regulators or active substances for treating obesity, such as
sibutramine or tetrahydrolipostatin, dexfenfluramine, axokine,
antagonists of the cannabinoidi receptor, MCH-1 receptor
antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists or
.beta.3-agonists such as SB-418790 or AD-9677 and agonists of the
5HT2c receptor.
[0307] Moreover, combinations with drugs for influencing high blood
pressure, chronic heart failure or atherosclerosis such as e.g.
A-II antagonists or ACE inhibitors, ECE inhibitors, diuretics,
.beta.-blockers, Ca-antagonists, centrally acting
antihypertensives, antagonists of the alpha-2-adrenergic receptor,
inhibitors of neutral endopeptidase, thrombocyte aggregation
inhibitors and others or combinations thereof are suitable.
Examples of angiotensin II receptor antagonists are candesartan
cilexetil, potassium losartan, eprosartan mesylate, valsartan,
telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312, olmesartan,
medoxomil, tasosartan, KT-3-671, GA-01 13, RU-64276, EMD-90423,
BR-9701, etc. Angiotensin II receptor antagonists are preferably
used for the treatment or prevention of high blood pressure and
complications of diabetes, often combined with a diuretic such as
hydrochlorothiazide.
[0308] A combination with uric acid synthesis inhibitors or
uricosurics is suitable for the treatment or prevention of
gout.
[0309] A combination with GABA-receptor antagonists, Na-channel
blockers, topiramat, protein-kinase C inhibitors, advanced
glycation end product inhibitors or aldose reductase inhibitors may
be used for the treatment or prevention of complications of
diabetes.
[0310] Such combinations may offer significant advantages,
including synergistic activity, in therapy.
[0311] The present invention is also in relation to a
pharmaceutical composition comprising a compound of formula 1 or
its prodrug and pharmaceutically acceptable excipients.
[0312] In still another embodiment of the present invention, the
prodrug is selected from a group comprising, esters and
hydrates.
[0313] The term pro-drug is also meant to include any covalently
bonded carries which release the active compound of the invention
in vivo when such prodrug is administered to a mammalian subject.
Pro-drugs of a compound of the invention may be prepared by
modifying functional groups present in the compound of the
invention in such a way that the modifications are cleaved, either
in routine manipulation or in vivo, to the parent compound of the
invention.
[0314] In still another embodiment of the present invention, the
excipients are selected from a group comprising, binders,
anti-adherents, disintegrants, fillers, diluents, flavors, colors,
glidants, lubricants, preservatives, sorbents and sweeteners or
combination(s) thereof.
[0315] In still another embodiment of the present invention, the
composition is formulated into various dosage forms selected from a
group comprising tablet, troches, lozenges, aqueous or oily
suspensions, ointment, patch, gel, lotion, dentifrice, capsule,
emulsion, creams, spray, drops, dispersible powders or granules,
emulsion in hard or soft gel capsules, syrups and elixirs.
[0316] Dosages of agents of the invention employed in practicing
the present invention will of course vary depending, for example,
on the particular condition to be treated, the effect desired and
the mode of administration. In general, suitable daily dosages for
oral administration are of the order of 0.1 to 10 mg/kg.
Method of Preparation
[0317] The invention provides, in another aspect, a process for
preparing a compound of formula (I). The schemes detailed below
show general schemes for synthesizing compounds of formula (I).
##STR00014##
[0318] Compounds of formula 1 wherein m.noteq.0 and all other
symbols are as defined herein above may be converted to compounds
of formula (2) wherein LG is a leaving group such as halide, tosyl
or mesyl. The reaction may be carried by methods reported in the
literature. Compounds of formula (2) may be reacted with Y--XH
wherein X is S and Y is as defined herein above in the presence of
a base and a solvent to provide compounds of formula (I) wherein
m.noteq.0, X is S and all other symbols are as defined herein
above. When X.dbd.S, it may be further oxidized to sulfinyl or
sulfonyl using suitable oxidation reagents and conditions well
known in the literature. Also, functional groups as substitutents
on Y may be transformed to different functional groups such as an
ester function being converted to an acid, amide, hydroxymethyl,
keto, aldehyde as well as an ester. The said conversions may be
carried out using reagents and conditions well documented in the
literature.
##STR00015##
[0319] Compounds of formula IV wherein m.noteq.0, X is S and all
other symbols are as defined herein above may be reacted with Y-LG
wherein LG is a leaving group such as halide, tosyl or mesyl. The
reaction may be carried in the presence of a base and a solvent to
provide compounds of formula (I) wherein m.noteq.0, X is S and all
other symbols are as defined herein above. When X.dbd.S, it may be
further oxidized to sulfinyl or sulfonyl using suitable oxidation
reagents and conditions well known in the literature. Also,
functional groups as substitutents on Y may be transformed to
different functional groups such as an ester function being
converted to an acid, amide, hydroxymethyl, keto, aldehyde as well
as an ester. The said conversions may be carried out using reagents
and conditions well documented in the literature.
[0320] Compounds of formula (I) may be prepared from other
compounds of formula (I) by methods well known to one skilled in
the art.
[0321] It will be understood that the processes detailed above and
elsewhere herein are solely for the purpose of illustrating the
invention and should not be construed as limiting. A process
utilising similar or analogous reagents and/or conditions known to
one skilled in the art may also be used to obtain a compound of the
invention.
[0322] Any mixtures of final products or intermediates obtained can
be separated on the basis of the physico-chemical differences of
the constituents, in a known manner, into the pure final products
or intermediates, for example by chromatography, distillation,
fractional crystallisation, or by the formation of a salt if
appropriate or possible under the circumstances.
[0323] The term "comprising" encompasses "including" as well as
"consisting" e.g. a composition "comprising" X may consist
exclusively of X or may include something additional e.g. X+Y.
[0324] The word "substantially" does not exclude "completely" e.g.
a composition which is "substantially free" from Y may be
completely free from Y. Where necessary, the word "substantially"
may be omitted from the definition of the invention. The term
"about" in relation to a numerical value x means, for example,
x.+-.10%.
[0325] The following Examples are intended to illustrate the
invention and are not to be construed as being limitations thereon.
If not mentioned otherwise, all evaporations are performed under
reduced pressure. The structure of final products, intermediates
and starting materials is confirmed by standard analytical methods,
e.g., microanalysis and spectroscopic characteristics, e.g. MS and
NMR. Abbreviations used are those conventional in the art.
EXAMPLE 1
(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-acetic acid methyl
ester
##STR00016##
[0327] Step I. To a mixture of
(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl--
tetrahydro-pyran-3,4,5-triol (500 mg, 0.98 mmole) (prepared
according to procedure as described in J. Med. Chem. 2008; 51 (5);
1145-1149), PPh.sub.3 (450 mg, 1.6 mmole) and imidazole (101 mg,
1.5 mmole) in dichloromethane (DCM, 20 mL) was added iodine (400
mg, 1.5 mmole) at 0.degree. C. and refluxed for 18 hrs. The
reaction mixture was diluted with water (50 mL) and extracted with
dichloromethane (2.times.200 mL). The crude product obtained after
the removal of solvent was purified using silica gel column
chromatography (0.5% methanol in DCM) to furnish 480 mg of
(2S,3R,4R,5S,6S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-iodo-
methyl-tetrahydro-pyran-3,4,5-triol.
[0328] Step II. To a solution of above compound (400 mg, 0.74
mmole) in DMF (2 mL), cesium carbonate (660 mg, 1.6 mmole) was
added followed by 4-mercaptophenylacetic acid methyl ester (176 mg,
0.89 mmole) at room temperature and stirred for 3-5 hours. The
reaction mixture was diluted with water (50 mL) and extracted with
DCM (2.times.200 mL). The crude product was purified by silica gel
column chromatography (1% methanol in DCM) to furnish 350 mg the
title compound.
[0329] .sup.1H-NMR (400 M Hz, CDCl.sub.3): .delta. 1.37 (t, J=7.2
Hz, 3H), 1.90 (s, 1H), 2.59 (s, 1H), 2.61 (s, 1H), 2.8 (s, 1H),
3.15 (m, 1H), 3.3-3.50 (m, 2H), 3.54 (s, 2H), 3.55-3.65 (m, 2H)
3.669 (s, 3H), 3.96-4.0 (m, 5H) 6.80 (d, J=8.4 Hz, 2H), 7.07 (m,
3H), 7.11 (d, J=1 Hz, 2H), 7.14 (s, 1H), 7.31-7.34 (m, 3H). MS (ES)
m/z 595 (M+Na).
EXAMPLE 2
(4-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-acetic acid
##STR00017##
[0331] To a solution of
(4-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-acetic acid
methyl ester (80 mg, 0.13 mmole) in a mixture of solvents
(THF-MeOH--H.sub.2O) (3:1:2, 5 mL) was added LiOH (15 mg, 0.26
mmole) and stirred for overnight at room temperature. The reaction
mixture was concentrated; acidified with 1N HCl and extracted with
DCM (2.times.50 mL). After the removal of solvent, the crude
product was purified by HPLC to furnish title compound.
[0332] .sup.1H-NMR (400 M Hz, CD.sub.3OD): .delta. 1.37 (t, J=7.2
Hz, 3H), 3.0 (m, 1H), 3.2 (m, 1H), 3.3-3.51 (m, 6H), 3.94-4.04 (m,
5H), 6.80 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 7.1-7.15 (m,
3H), 7.21 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 3H). MS (ES) m/z
576 (M+18).
EXAMPLE 3
(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-acetic acid
carboxamide
##STR00018##
[0334] The compound
(4-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-acetic acid
methyl ester (100 mg, 0.17 mmole) in methanolic ammonia (5.0 mL)
was heated in sealed tube at 80.degree. C. overnight. The reaction
mixture was concentrated and purified by HPLC to furnish 30 mg the
title compound.
[0335] .sup.1H-NMR (400 M Hz, CD.sub.3OD): .delta. 1.34 (t, J=7.2
Hz, 3H), 3.05-3.10 (m, 1H), 3.2 (m, 1H), 3.41-3.51 (m, 6H),
3.94-4.14 (m, 5H), 6.80 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H),
7.1-7.15 (m, 3H), 7.21 (d, J=8.0 Hz, 1H), 7.30 (m, 3H). MS (ES) m/z
558 (M+1).
EXAMPLE 4
2-(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihy-
droxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-N-methyl-acetamide
##STR00019##
[0337] The compound
(4-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-acetic acid
methyl ester (100 mg, 0.17 mmole) in 2M methanolic methylammonia
(5.0 mL) solution was heated in sealed tube at 80.degree. C.
overnight. The reaction mixture was concentrated to furnish the
title compound (80 mg).
[0338] .sup.1H-NMR (400 M Hz, CD.sub.3OD): .delta. 1.34 (t, J=7.2
Hz, 3H), 2.69 (s, 3H), 3.05-3.10 (m, 1H), 3.2 (m, 1H), 3.41-3.58
(m, 6H), 3.94-4.04 (m, 5H), 6.80 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.4
Hz, 2H), 7.09 (d, J=2.0 Hz, 1H), 7.13 (d, J=8.0 Hz, 2H), 7.20 (d,
J=2.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 2H). MS
(ES) m/z 558 (M+1).
EXAMPLE 5
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-[4-(2-hydroxy-e-
thyl)-phenylsulfanylmethyl]-tetrahydro-pyran-3,4,5-triol
##STR00020##
[0340] To a solution of
(4-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-acetic acid
methyl ester (80 mg, 0.14 mmole) in THF-Water-MeOH mixture (1:1:1,
5 mL) was added NaBH.sub.4 (10 mg, 0.27 mmole) and stirred for 6 h.
On completion, the reaction mixture was diluted with water (10 mL),
extracted with ethyl acetate (2.times.20 mL) and concentrated to
get the crude product which was further purified by silica gel
column chromatography (1% MeOH in DCM) to furnish the title
compound (50 mg).
[0341] .sup.1H-NMR (400 M Hz, CD.sub.3OD): .delta. 1.39 (t, J=7.2
Hz, 3H), 2.72 (t, J=7.2 Hz, 2H), 3.05-3.07 (m, 1H), 3.23 (t, J=9.2
Hz, 2H), 3.39-3.42 (m, 3H), 3.68 (t, J=7.2 Hz, 2H), 3.94-34.03 (m,
5H), 6.79 (d, J=8.4 Hz, 2H), 7.056 (dd, J=1.6 & 8.0 Hz, 4H),
7.099 (dd, J=1.6 & 8.0 Hz, 1H), 7.198 (d, J=2.0 Hz, 1H),
7.279-7.31 (m, 3H). MS (ES) m/z 562 (M+18).
EXAMPLE 6
(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethanesulfonyl}-phenyl)-acetic acid
methyl ester
##STR00021##
[0343] To a mixture of
(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethanesulfanyl}-phenyl)-acetic acid
methyl ester (120 mg, 0.20 mmole) in DCM (10 mL) was added
meta-chloroperbenzoic acid (m-CPBA) (72 mg, 0.41 mmole) at
0.degree. C. and stirred for 3 h. at room temperature. The reaction
mixture was diluted with water (10 mL) and extracted with
dichloromethane (2.times.20 mL) and the organic layer washed with
saturated solution of sodium bicarbonate (10 mL). The crude product
obtained after the removal of solvent was purified by HPLC to
furnish 120 mg of title compound.
[0344] .sup.1H-NMR (400 M Hz, CDCl.sub.3): .delta. 1.35 (t, J=7.2
Hz, 3H), 3.07-3.17 (m, 2H), 3.22-3.26 (m, 5H), 3.35-3.49 (m, 2H),
3.69 (s, 3H), 3.74 (t, J=9.2 Hz, 1H), 3.82 (d, J=9.6 Hz, 1H), 3.90
(d, J=13.2 Hz, 1H), 3.98 (q, J=6.8 Hz, 2H), 6.78 (dd, J=2.0, 8.0
Hz, 1H), 6.84 (d, J=8.8 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 7.01 (d,
J=1.6 Hz, 1H), 7.15-7.25 (d, J=8.8 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H)
7.60 (d, J=8.0 Hz, 2H). MS (ES) m/z 605 (M+1).
EXAMPLE 7
(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,6-trihydr-
oxy-tetrahydro-pyran-2-ylmethanesulfonyl}-phenyl)-acetic acid
##STR00022##
[0346] Title compound was prepared according to the procedure as
described in example 2.
[0347] .sup.1H-NMR (400 M Hz, CD.sub.3OD): .delta. 1.35 (t, J=7.2
Hz, 3H), 3.14 (m, 2H), 3.30-3.50 (m, 4H), 3.62 (d, J=14.4 Hz, 1H),
3.73 (t, J=9.2 Hz, 1H), 3.83 (d, J=9.2 Hz, 1H), 3.90-4.08 (m, 4H),
6.80 (dd, J=1.6, 8.4 Hz, 1H), 6.84 (d, J=8.4 Hz, 2H), 6.95-7.02 (m,
3H), 7.16 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz, 1H), 7.59 (d, J=8.0
Hz, 2H). MS (ES) m/z 591 (M+1).
[0348] Following examples were obtained using analogous procedures
described above.
EXAMPLE 8
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-(pyrimidin-2-yl-
sulfanylmethyl)-tetrahydro-pyran-3,4,5-triol
##STR00023##
[0350] .sup.1H-NMR (400 M Hz, CD.sub.3OD): .delta. 1.35 (t, J=7.2
Hz, 3H), 3.22 (t, J=9.2 Hz, 2H), 3.30-3.45 (m, 3H), 3.61-3.62 (m,
1H), 3.85-3.95 (d, J=14.4 Hz, 1H), 3.94-3.99 (m, 3H), 4.09 (d,
J=9.36 Hz, 1H), 6.81 (d, J=8.8 Hz, 2H), 7.05-7.11 (m, 2H), 7.14 (d,
J=8.0 Hz, 1H), 7.20 (s, 1H), 7.30 (d, J=8.4 Hz, 2H), 8.52 (d, J=4.8
Hz, 2H). MS (ES) m/z 503 (M+1)
EXAMPLE 9
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-(thiazol-2-ylsu-
lfanylmethyl)-tetrahydro-pyran-3,4,5-triol
##STR00024##
[0352] .sup.1H-NMR (400 M Hz, CD.sub.3OD): .delta. 1.35 (t, J=7.2
Hz, 3H), 3.18-3.23 (m, 1H), 3.29-3.50 (m, 3H), 3.61 (m, 2H),
3.94-4.079 (m, 4H), 4.07 (d, J=9.2 Hz, 1H), 6.81 (d, J=8.8 Hz, 2H),
7.05-7.11 (m, 3H), 7.15 (s, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.35 (d,
J=3.6 Hz, 1H), 7.58 (d, J=3.6 Hz, 1H). MS (ES) m/z 508 (M+1).
EXAMPLE 10
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-(1-methyl-1H-te-
trazol-5-ylsulfanylmethyl)-tetrahydro-pyran-3,4,5-triol
##STR00025##
[0354] .sup.1H-NMR (400 M Hz, CD.sub.3OD): .delta. 1.35 (1, J=7.2
Hz, 3H), 3.196 (m, 1H), 3.30-3.50 (m, 3H), 3.57-3.60 (m, 1H),
3.73-3.788 (dd, J=2.4 & 14 Hz, 1H), 3.80 (s, 3H), 3.95-4.0 (m,
5H), 6.81 (d, J=8.8 Hz, 2H), 7.01 (dd, J=8.4 Hz, 1H), 7.02 (s, 1H),
7.09 (d, J=8.4 Hz, 2H), 7.29 (d, J=8.0 Hz, 1H). MS (ES) m/z 507
(M+1).
EXAMPLE 11
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-(thiophen-2-yls-
ulfanylmethyl)-tetrahydro-pyran-3,4,5-triol
##STR00026##
[0356] .sup.1H-NMR (400 M Hz, CD.sub.3OD): .delta. 1.34 (t, J=7.2
Hz, 3H), 2.96 (m, 2H), 3.13 (m, 1H), 3.30-3.47 (m, 3H), 3.96-4.03
(m, 5H), 6.79 (d, J=8.8 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 6.87 (dd,
J=5.6 & 4.0 Hz, 1H), 7.07-7.7.09 (m, 2H), 7.16 (dd, J=1.6 &
8.0 Hz, 2H), 7.33 (d, J=3.6 Hz, 1H). MS (ES) m/z 507 (M+1).
EXAMPLE 12
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-(5-methyl-1,1-d-
ioxo-1H-1lambda*6*-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-tetrahydro-pyran--
3,4,5-triol
##STR00027##
[0358] .sup.1H-NMR (400 M Hz, CD.sub.3OD): .delta. 1.35 (t, J=7.2
Hz, 3H), 2.58 (s, 3H), 3.23 (t, J=8.8 Hz, 1H), 3.3-3.47 (m, 3H),
3.64-3.68 (m, 2H), 3.9-4.07 (m, 5H), 6.81 (d, J=8.8 Hz, 2H), 7.03
(d, J=2.0 Hz, 1H), 7.06 (m, 2H), 7.12 (s, 1H), 7.31 (d, J=8.0 Hz,
1H). MS (ES) m/z 555 (M+1).
EXAMPLE 13
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-(4-phenyl-thioz-
ol-2-ylsulfanylmethyl)-tetrahydro-pyran-3,4,6-triol
##STR00028##
[0360] .sup.1H-NMR (400 M Hz, CDCl.sub.3): .delta. 1.40 (t, J=7.2
Hz, 3H), 2.18 (bs, 1H), 2.91 (bs, 1H), 3.43-3.50 (m, 2H), 3.71-3.77
(m, 3H), 3.98-4.08 (m, 5H), 4.21 (d, J=9.2 Hz, 1H), 6.08 (bs, 1H),
6.81 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.8 Hz, 2H), 7.16-7.22 (m, 2H),
7.31-7.38 (m, 3H), 7.41-7.45 (m, 2H), 7.71-7.73 (m, J=7.2 Hz, 2H).
MS (ES) m/z 584 (M+1).
EXAMPLE 14
(2S,3S,4R,5R,6S)-2-(Benzothiazol-2-ylsulfanylmethyl)-6-[4-chloro-3-(4-etho-
xy-benzyl)-phenyl]-tetrahydro-pyran-3,4,5-triol
##STR00029##
[0362] .sup.1H-NMR (400 M Hz, CDCl.sub.3): .delta. 1.40 (t, J=7.2
Hz, 3H), 2.18 (bs, 1H), 2.91 (bs, 1H), 3.48-3.51 (m, 2H), 3.60-3.64
(t, J=9.2 Hz, 1H), 3.72-3.80 (m, 2H), 3.98-4.14 (m, 5H), 4.21 (d,
J=9.2 Hz, 1H), 6.25 (bs, 1H), 6.81 (d, J=8.8 Hz, 2H), 7.08 (d,
J=8.8 Hz, 2H), 7.17-7.22 (m, 2H), 7.31-7.45 (m, 3H), 7.74-7.78 (m,
2H). MS (ES) m/z 558 (M+1).
EXAMPLE 15
(2S,3S,4R,5R,6S)-2-(1H-Benzoimidazol-2-ylsulfanylmethyl)-6-[4-chloro-3-(4--
ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3,4,5-triol
##STR00030##
[0364] .sup.1H-NMR (400 M Hz, CD.sub.3OD): .delta. 1.35 (t, J=6.8
Hz, 3H), 3.22 (m, 1H), 3.45-3.49 (m, 2H), 3.61 (m, 1H), 3.67-3.72
(m, 3H), 3.86-3.99 (m, 3H), 4.05 (d, J=9.2 Hz, 1H), 6.76-6.79 (m,
3H), 6.92 (d, J=8 Hz, 1H), 6.96-7.00 (m, 3H), 7.26-7.33 (m, 4H). MS
(ES) m/z 541 (M+1).
EXAMPLE 16
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-(5-trifluoromet-
hyl-pyridin-2-ylsulfanylmethyl)-tetrahydro-pyran-3,4,5-triol
##STR00031##
[0366] .sup.1H-NMR (400 M Hz, CD.sub.3OD): .delta.1.35 (t, J=7.2
Hz, 3H), 3.22 (t, J=9.2 Hz, 1H), 3.41-3.50 (m, 3H), 3.50-3.60 (m,
1H), 3.80-3.84 (m, 1H), 3.92-4.03 (m, 4H), 4.05 (d, J=9.6 Hz, 1H),
6.81 (d, J=8.4 Hz, 2H), 7.05-7.11 (m, 3H), 7.18 (bs, 1H), 7.26-7.29
(d, J=8.4 Hz, 1H), 7.46-7.48 (d, J=8.4 Hz, 1H), 7.77-7.79 (m, 1H),
8.65 (bs, 1H). MS (ES) m/z 570 (M+1).
EXAMPLE 17
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-(pyrimidin-2-yl-
sulfonylmethyl)-tetrahydro-pyran-3,4,5-triol
##STR00032##
[0368] .sup.1H-NMR (400 M Hz, CD.sub.3OD): .delta. 1.36 (t, J=7.2
Hz, 3H), 3.11 (t, J=9.2 Hz, 1H), J=9.2 Hz, 1H), 3.35 (t, J=8.8 Hz,
1H), 3.64-3.79 (m, 3H), 3.90-4.06 (m, 5H), 6.70 (dd, J.sub.1=2 Hz,
J.sub.2=8.4 Hz 1H), 6.85-6.91 (m, 4H), 7.19 (d, J=8.4 Hz, 2H), 7.25
(d, J=8.0 Hz, 1H), 8.32 (d, J=4.8 Hz, 2H). MS (ES) m/z 535
(M+1)
EXAMPLE 18
4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydro-
xy-tetrahydro-pyran-2-ylmethylsulfanyl}-benzoic acid ethyl
ester
##STR00033##
[0370] .sup.1H-NMR (400 M Hz, CD.sub.3OD): .delta. 1.37 (m, 6H),
3.17-3.21 (m, 2H), 3.42-3.47 (m, 2H), 3.55-3.59 (m, 2H), 3.90-4.04
(m, 5H), 4.31 (q, J=6.8 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 7.01 (d,
J=8.8 Hz, 3H), 7.11 (m, 1H), 7.22-7.24 (d, J=8.0 Hz, 1H), 7.41 (d,
J=8.8 Hz, 2H), 7.79 (d, J=8.8 Hz, 2H). MS (ES) m/z 573 (M+1).
EXAMPLE 19
4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydro-
xy-tetrahydro-pyran-2-ylmethylsulfanyl}-benzoic acid
##STR00034##
[0372] .sup.1H-NMR (400 M Hz, CD.sub.3OD): .delta. 1.35 (t, J=7.2
Hz, 3H), 3.18-3.22 (m, 2H), 3.42-3.47 (m, 2H), 3.55-3.59 (m, 2H),
3.88-4.05 (m, 5H), 6.76 (d, J=8.8 Hz, 2H), 7.03-7.06 (m, 3H), 7.13
(m, 1H), 7.25-7.27 (d, J=8.4 Hz, 1H), 7.41-7.43 (d, J=8.4 Hz, 2H),
7.82-7.84 (d, J=8.4 Hz, 2H). MS (ES) m/z 545 (M+1).
EXAMPLE 20
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-(4-hydroxymethy-
l-phenylsulfanylmethyl)-tetrahydro-pyran-3,4,5-triol
##STR00035##
[0374] .sup.1H-NMR (400 M Hz, CD.sub.3OD): .delta. 1.36 (t, J=7.2
Hz, 3H), 3.1 (dd, J=7.2 Hz, 6.8 Hz, 1H), 3.21 (m, 1H), 3.40-3.55
(m, 4H), 3.92-4.04 (m, 5H), 4.51 (s, 2H), 6.78 (d, J=8.4 Hz, 2H),
7.06-7.11 (m, 3H), 7.18-7.20 (m, 3H), 7.28-7.30 (d, J=8.0 Hz, 1H),
7.34-7.37 (d, J=8.4 Hz, 2H). MS (ES) m/z 548 (M+18).
EXAMPLE 21
6-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydro-
xy-tetrahydro-pyran-2-ylmethylsulfanyl}-nicotinic acid
##STR00036##
[0376] .sup.1H-NMR (400 M Hz, CD.sub.3OD): .delta. 1.35 (t, J=7.2
Hz, 3H), 3.22 (t, J=9.2 Hz, 1H), 3.41-3.53 (m, 3H), 3.62 (m, 1H),
3.74-3.78 (m, 1H), 3.92-4.03 (m, 4H), 4.05 (d, J=9.6 Hz, 1H), 6.88
(d, J=8.8 Hz, 2H), 7.04-7.11 (m, 3H), 7.16 (bs, 1H), 7.26-7.28 (d,
J=8.4 Hz, 1H), 7.40-7.42 (d, J=8.4 Hz, 1H), 8.03-8.06 (m, 1H), 8.90
(bs, 1H).
[0377] MS (ES) m/z 546 (M+1)
EXAMPLE 22
2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydro-
xy-tetrahydro-pyran-2-ylmethylsulfanyl}-benzoic acid
##STR00037##
[0379] .sup.1H-NMR (400 M Hz, CD.sub.3OD): .delta. 1.34 (t, J=7.2
Hz, 3H), 3.05-3.11 (dd, J=7.6 Hz, 6.4 Hz, 1H), 3.23 (t, J=9.2 Hz,
1H), 3.40-3.52 (m, 3H), 3.58-3.60 (m, 1H), 3.91-3.98 (m, 4H), 4.05
(d, J=9.6 Hz, 1H), 6.76 (d, J=8.8 Hz, 2H), 7.03-7.05 (d, J=8.8 Hz,
2H), 7.09-7.15 (m, 2H), 7.20 (bs, 1H), 7.26-7.28 (d, J=8.4 Hz, 1H),
7.32-7.36 (m, 1H), 7.54-7.56 (d, J=8.4 Hz, 1H), 7.87-7.89 (m, 1H).
MS (ES) m/z 545 (M+1).
EXAMPLE 23
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-(2-hydroxymethy-
l-phenylsulfanylmethyl)-tetrahydro-pyran-3,4,5-triol
##STR00038##
[0381] .sup.1H-NMR (400 M Hz, CD.sub.3OD): .delta. 1.34 (t, J=7.2
Hz, 3H), 3.03-3.13 (m, 1H), 3.26 (t, J=9.2 Hz, 1H), 3.39-3.54 (m,
4H), 3.73-3.77 (m, 1H), 3.85-3.88 (m, 1H), 3.94-4.02 (m, 4H), 4.09
(d, J=9.6 Hz, 1H), 6.80 (d, J=8.8 Hz, 2H), 7.06-7.10 (m, 3H),
7.14-7.18 (m, 1H), 7.22-7.25 (m, 2H), 7.28-7.38 (m, 2H), 7.47-7.50
(m, 1H).
[0382] MS (ES) m/z 548 (M+18).
EXAMPLE 24
2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydro-
xy-tetrahydro-pyran-2-ylmethylsulfanyl}-benzamide
##STR00039##
[0384] .sup.1H-NMR (400 M Hz, CD.sub.3OD): .delta. 1.34 (t, J=7.2
Hz, 3H), 3.09-3.14 (dd, J=7.2 Hz, 6.4 Hz, 1H), 3.23 (t, J=9.2 Hz,
1H), 3.41-3.56 (m, 4H), 3.95-4.05 (m, 5H), 6.78 (d, J=8.8 Hz, 2H),
7.06-7.08 (d, J=8.8 Hz, 2H), 7.11-7.20 (m, 3H), 7.25-7.31 (m, 2H),
7.39-7.41 (m, 1H), 7.56-7.58 (d, J=8.0 Hz, 1H). MS (ES) m/z 544
(M+1).
EXAMPLE 25
N-(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihy-
droxy-tetrahydro-pyran-2-ylmethylsulfanyl}-4-fluoro-phenyl)-acetamide
##STR00040##
[0386] Step I. Thionyl chloride (12 mL) was added to water (72 mL)
under ice cooling and stirred at room temperature for 18 hrs.
Copper(I) chloride (42 mg) was added at -3 to 0.degree. C. and
resulting yellowish green solution was stored at -3.degree. C.
[0387] Step II. To a mixture of 2-fluoro-5-nitroaniline (2.0 g,
12.8 mmole) in conc. HCl (15 mL) NaNO.sub.2 solution (1.05 g, 15.3
mmole, in 1.5 mL water) added at -10.degree. C. and stirred for 1
hour to get yellow diazonium salt.
[0388] Step III. Above Diazonium salt obtained in step II was added
dropwise to the solution obtained in step I at -10 to 0.degree. C.
and stirred for 1 hour at 0.degree. C. and 30 min at room
temperature. The reaction mixture was diluted with water (250 mL)
and extracted with diethyl ether (3.times.25 mL), resulting organic
layer washed with saturated sodium bicarbonate (25.times.2 mL).
Removal of solvent furnished 2-fluoro-5-nitro-benzenesulfonyl
chloride (1.4 g).
[0389] Step IV. To a mixture of 2-fluoro-5-nitro-benzenesulfonyl
chloride (1.4 g, 5.85 mmole) in conc. HCl (7 mL),
SnCl.sub.2.2H.sub.2O (6.6 g, 29.2 mmole) was added and reaction
mixture heated to 100.degree. C. The reaction mixture was cooled to
room temperature and conc. HCl (3 mL) was added and filtered
through celite bed, filtrate was basified with saturated sodium
bicarbonate and extracted with dichloromethane (2.times.25 mL).
Removal of solvent furnished crude 2-fluoro-5-amino-benzenethiol
(0.48 g) which was used as such for the next step.
[0390] Step V. To an ice cold solution of
(2S,3R,4R,5S,6S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-iodomethyl-tet-
rahydro-pyran-3,4,5-triol (150 mg, 0.28 mmole) in DMF (2 mL),
cesium carbonate (182 mg, 0.56 mmole) was added followed by crude
2-fluoro-5-amino-benzenethiol (200 mg, 1.12 mmole) at room
temperature and stirred for 5 hrs. The reaction mixture was diluted
with water (50 mL) and extracted with dichloromethane (2.times.20
mL). The crude product was purified by silica gel column
chromatography (1% methanol in dichloromethane) to furnish
(2S,3S,4R,5R,6S)-2-(5-amino-2-fluoro-phenylsulfanylmethyl)-6-[4-chloro-3--
(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3,4,5-triol (85 mg).
[0391] Step VI. To a solution of
(2S,3S,4R,5R,6S)-2-(5-amino-2-fluoro-phenylsulfanylmethyl)-6-[4-chloro-3--
(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3,4,5-triol (60 mg, 0.11
mmole) in pyridine (0.5 mL), acetic anhydride (0.3 mL), DMAP (1 mg)
was added at room temperature and stirred overnight. The reaction
mixture was diluted with water (10 mL) and acidified with 1N HCl,
extracted with dichloromethane (2.times.20 mL). The product
obtained after the removal of solvent furnished acetic acid
(2S,3S,4R,5S,6S)-4,5-diacetoxy-2-(5-amino-2-fluoro-phenylsulfanylmethyl)--
6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3-yl ester
(85 mg).
[0392] Step VII. To a solution of acetic acid
(2S,3S,4R,5S,6S)-4,5-diacetoxy-2-(5-amino-2-fluoro-phenylsulfanylmethyl)--
6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3-yl ester
(85 mg, 0.12 mmole) in THF:MeOH:H.sub.2O (3:1:2, 13 mL), lithium
hydroxide (10 mg, 0.24 mmole) was added room temperature and
stirred overnight. The reaction mixture was diluted with water (10
mL) and extracted with dichloromethane (3.times.20 mL). The crude
product obtained after the removal of solvent was purified using
preparative HPLC to furnish
N-(3-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-4-fluoro-phenyl)-acetamide
(20 mg).
[0393] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.37 (t, J=7.2
Hz, 3H), 2.06 (s, 3H), 3.11-3.22 (m, 2H), 3.41-3.52 (m, 3H), 3.59
(t, J=6.8 Hz, 1H), 3.91-4.05 (m, 5H), 6.81 (d, J=8.8 Hz, 2H), 6.92
(t, J=9.6 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 7.07 (d, J=8.4 Hz, 2H),
7.12 (s, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.35-7.38 (m, 1H), 7.70 (dd,
J=2.0 & 6.4 Hz, 1H).
[0394] MS (ES) m/z 576.1 (M+H).
EXAMPLE 26
3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,6-trihydro-
xy-tetrahydro-pyran-2-ylmethylsulfanyl}-4-fluoro-benzamide
##STR00041##
[0396] Step I. 4-Fluorobenzoic acid (3.0 g, 21.4 mmole) was added
to ice cold solution of chlorosulfonic acid (9.0 mL). Reaction
mixture was stirred at 130-140.degree. C. for 8 hours. Reaction
mixture added slowly to ice water (250 mL) and extracted with
dichloromethane (3.times.25 mL). The crude product obtained after
the removal of solvent furnished 3-chlorosulfonyl-4-fluoro-benzoic
acid (3.3 g).
[0397] Step II. To a mixture of 3-chlorosulfonyl-4-fluoro-benzoic
acid (3.2 g, 1.34 mmole) in conc. HCl (10 mL), SnCl.sub.2.2H.sub.2O
(9.0 g, 4.0 mmole) was added and reaction mixture heated to
100.degree. C. The reaction mixture was diluted with water (50 mL)
and basified with saturated sodium bicarbonate, inorganic material
was filtered and filtrate was acidified with 1N HCl and extracted
with dichloromethane (4.times.25 mL). Solvent removal furnished
4-fluoro-3-mercapto-benzoic acid (2.5 g).
[0398] Step III. To a mixture of 4-fluoro-3-mercapto-benzoic acid
(2.4 g, 13.9 mmole) in methanol, thionyl chloride (3.0 mL) was
added at 0.degree. C. and reaction mixture heated to 70.degree. C.
The reaction mixture was diluted with water (50 mL) extracted with
ethyl acetate (3.times.25 mL). Solvent removal furnished crude
4-fluoro-3-mercapto-benzoic acid methyl ester (2.0 g).
[0399] Step IV. To an ice cold solution of
(2S,3R,4R,5S,6S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-iodomethyl-tet-
rahydro-pyran-3,4,5-triol (100 mg, 0.19 mmole) in DMF (2 mL),
cesium carbonate (125 mg, 0.38 mmole) was added followed by of
4-fluoro-3-mercapto-benzoic acid methyl ester (53 mg, 0.28 mmole)
at room temperature and stirred for 5 hours. The reaction mixture
was diluted with water (50 mL) and extracted with dichloromethane,
(2.times.20 mL). The crude product was purified by silica gel
column chromatography (1% methanol in dichloromethane) to furnish
3-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-4-fluoro-benzoic acid
methyl ester (80 mg).
[0400] Step IV. To a solution of
3-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-4-fluoro-benzoic acid
methyl ester (0.3 g, 0.52 mmole) in a mixture of solvents
(THF-MeOH--H.sub.2O) (3:1:2, 6 mL) was added LiOH (43 mg, 1.0
mmole) and stirred overnight at room temperature. The reaction
mixture was concentrated; acidified with 1N HCl and extracted with
dichloromethane (2.times.50 mL). Solvent removal furnished
3-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-4-fluoro-benzoic acid (210
mg).
[0401] Step V. To a solution of
3-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-4-fluoro-benzoic acid (100
mg, 0.17 mmole) in DMF (1 mL), HOBt (28 mg, 0.21 mmole) was added
and stirred for 10 min., EDCl (40 mg, 0.21 mmole) was added and
stirred at room temperature overnight. The reaction mixture was
diluted with water (10 mL) and extracted with ethyl acetate (20
mL.times.2). The crude product obtained after the removal of
solvent was purified using preparative HPLC to furnish
3-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-4-fluoro-benzamide (30
mg).
[0402] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.38 (t, J=8.4
Hz, 3H), 3.21 (t, J=9.2 Hz, 2H), 3.41-3.52 (m, 3H), 3.62 (t, J=7.6
Hz, 1H), 3.93-4.06 (m, 5H), 6.82 (d, J=8.4 Hz, 2H), 7.00 (t, J=8.4
Hz, 2H), 7.10 (d, J=8.8 Hz, 3H), 7.28 (d, J=8.4 Hz, 1H),
7.62-7.7.68 (m, 1H), 8.06 (d, J=6.8 Hz, 1H). MS (ES) m/z 562.0
(M+H).
EXAMPLE 27
3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydro-
xy-tetrahydro-pyran-2-ylmethylsulfanyl}-4-fluoro-N-methyl-benzamide
##STR00042##
[0404] To a solution of
3-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-4-fluoro-benzoic acid
methyl ester (80 mg, 0.13 mmole) in 2M methanolic methylammonia
(5.0 mL), 1,5,7 triazo bicycle[4,4,0] dec-5-ene (19 mg, 0.13) was
added and heated in sealed tube at 90.degree. C. for 72 hours. The
reaction mixture was concentrated and purified by preparative HPLC
to furnish
3-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-4-fluoro-N-methyl-benzamide
(8.0 mg).
[0405] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.38 (t, J=8.4
Hz, 3H), 2.86 (s, 3H), 3.20 (dd, J=6.0 & 14.4 Hz, 2H),
3.41-3.52 (m, 3H), 3.60 (t, J=7.2 Hz, 1H), 3.90-4.04 (m, 5H), 6.80
(d, J=8.4 Hz, 2H), 6.97-7.00 (m, 2H), 7.05 (d, J=3.6 Hz, 1H), 7.07
(d, J=3.6 Hz, 2H), 7.25 (d, J=8.4 Hz, 1H), 7.59-7.62 (m, 1H), 7.99
(dd, J=1.6 & 6.8 Hz, 1H).
[0406] MS (ES) m/z 576.0 (M+H).
EXAMPLE 28
(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-tri
hydroxy-tetrahydro-pyran-2-ylmethanesulfinyl}-phenyl)-acetic
acid
##STR00043##
[0408] Step I. A solution of
(4-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-acetic acid
methyl ester (100 mg, 0.17 mmole) in hexafluoroisopropanol (1 mL),
50% aqueous H.sub.2O.sub.2 (20 .mu.L, 0.34 mmole) at 0.degree. C.
and stirred for 2 hours. The reaction mixture was diluted with
water (10 mL) and washed with aqueous sodium metabisulfide (2 mL),
extracted with ethyl acetate (2.times.20 mL), removal of solvent
furnished crude
(4-(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethanesulfinyl}-phenyl)-acetic acid
methyl ester (100 mg).
[0409] Step II. To a solution of
(4-(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethanesulfinyl}-phenyl)-acetic acid
methyl ester (100 mg, 0.17 mmole) in THF:MeOH:H.sub.2O (3 mL),
lithium hydroxide (15 mg, 0.34 mmole) was added at room temperature
and stirred overnight. The reaction mixture was diluted with water
(10 mL) and extracted with ethyl acetate (3.times.20 mL). The crude
product obtained after the removal of solvent was purified using
preparative HPLC to furnish
(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethanesulfinyl}-phenyl)-acetic acid (90
mg).
[0410] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.38 (t, J=8.4
Hz, 3H), 2.96-3.02 (m, 1H), 3.24-3.31 (m, 1H), 3.39 (t, J=6.8 Hz,
1H), 3.50 (t, J=8.8 Hz, 1H), 3.55 (s, 1H), 3.68 (s, 1H), 3.84 (d,
J=9.2 Hz, 1H), 3.97-4.12 (m, 5H), 4.18 (d, J=9.6 Hz, 1H), 6.85 (t,
J=8.0 Hz, 2H), 7.12-7.18 (m, 3H), 7.27 (d, J=7.6 Hz, 1H), 7.31 (d,
J=8.0 Hz, 1H), 7.37 (t, J=8.4 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.51
(d, J=8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H).MS (ES) m/z 575.2
(M+H).
EXAMPLE 29
(2S,3S,4R,5R,6S)-2-(2-Amino-phenylsulfanylmethyl)-6-[4-chloro-3-(4-ethoxy--
benzyl)-phenyl]-tetrahydro-pyran-3,4,5-triol
##STR00044##
[0412] Title compound was prepared according to the procedure as
described in example 1.
[0413] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.38 (t, J=7.0
Hz, 3H), 3.19-3.25 (m, 2H), 3.34-3.50 (m, 2H), 3.53-3.64 (m, 2H),
3.96-4.09 (m, 5H), 6.80 (d, J=8.0 Hz, 2H), 7.07 (d, J=8.0 Hz, 3H),
7.18 (d, J=1.2 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.45 (d, J=8.0 Hz,
2H), 7.75 (d, J=8.0 Hz, 2H).
[0414] MS (ES) m/z 516.1 (M+H).
EXAMPLE 30
(2S,3S,4R,5R,6S)-2-(3-Amino-phenylsulfanylmethyl)-6-[4-chloro-3-(4-ethoxy--
benzyl)-phenyl]-tetrahydro-pyran-3,4,5-triol
##STR00045##
[0416] Title compound was prepared according to the procedure as
described in example 1.
[0417] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.37 (t, J=7.2
Hz, 3H), 2.92-2.98 (m, 1H), 3.09-3.13 (m, 1H), 3.21-3.30 (m, 3H),
3.5 (m, 2H), 3.94-4.03 (m, 4H), 4.95 (d, J=6.0 Hz, 1H), 5.08-5.10
(m, 3H), 5.29 (d, J=5.2 Hz, 1H), 6.35 (d, J=7.6 Hz, 1H), 6.45 (d,
J=7.6 Hz, 1H), 6.52 (s, 1H), 6.83 (d, J=8.4 Hz, 2H), 6.91 (t, J=8.0
Hz, 1H), 7.10 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.4 Hz, 1H), 7.27 (s,
1H), 7.36 (d, J=8.4 Hz, 1H).
[0418] MS (ES) m/z 516.0 (M+H).
EXAMPLE 31
(2S,3S,4R,5R,6S)-2-(4-Amino-phenylsulfanylmethyl)-6-[4-chloro-3-(4-ethoxy--
benzyl)-phenyl]-tetrahydro-pyran-3,4,5-triol
##STR00046##
[0420] Title compound was prepared according to the procedure as
described in example 1.
[0421] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.38 (t, J=7.0
Hz, 3H), 2.92 (dd, J=6.8, 13.6 Hz, 1H), 3.22-3.31 (m, 2H),
3.41-3.46 (m, 3H), 3.98-4.10 (m, 5H), 6.59 (d, J=8.0 Hz, 2H), 6.83
(d, J=8.0 Hz, 2H), 7.14 (d, J=8.0 Hz, 3H), 7.20 (d, J=8.0 Hz, 2H),
7.25 (br s, 1H), 7.36 (d, J=8.0 Hz, 1H).
[0422] MS (ES) m/z 516.1 (M+H).
EXAMPLE 32
(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-acetic acid
##STR00047##
[0424] Title compound was prepared according to the procedure as
described in example 2.
[0425] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.34 (t, J=7.2
Hz, 3H), 3.08 (dd, J=6.8 & 13.6 Hz, 1H), 3.21 (t, J=9.2 Hz,
1H), 3.38-3.53 (m, 6H), 3.92-4.04 (m, 5H), 6.78 (d, J=8.8 Hz, 2H),
7.01-7.1.7 (m, 6H), 7.28 (t, J=8.0 Hz, 3H).
[0426] MS (ES) m/z 576.3 (M+18).
EXAMPLE 33
(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-acetic acid
##STR00048##
[0428] Title compound was prepared according to the procedure as
described in example 2.
[0429] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.33 (t, J=7.2
Hz, 3H), 3.04 (t, J=9.2 Hz, 1H), 3.14 (t, J=9.2 Hz, 1H), 3.18-3.29
(m, 1H), 3.36 (t, J=9.2 Hz, 1H), 3.46-3.52 (m, 1H), 3.60-3.65 (m,
1H), 3.73 (t, J=9.6 Hz, 1H), 3.83 (s, 1H), 3.86 (d, J=5.2 Hz, 1H),
3.90 (s, 1H), 3.96 (q, J=7.2 Hz, 2H), 3.98 (d, J=6.8 Hz, 1H),
6.78-6.82 (m, 3H), 6.93 (d, J=2.0 Hz, 1H), 7.04-7.11 (m, 3H), 7.16
(d, J=8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H),
7.62 (s, 1H).
[0430] MS (ES) m/z 591.3 (M+H).
EXAMPLE 34
2-(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihy-
droxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-acetamide
##STR00049##
[0432] Title compound was prepared according to the procedure as
described in example 3.
[0433] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.34 (t, J=7.2
Hz, 3H), 3.10 (dd, J=6.8, 14 Hz, 1H), 3.21 (t, J=8.8 Hz, 1H),
3.38-3.48 (m, 5H), 3.54 (t, J=9.6 Hz, 1H), 3.92-4.04 (m, 5H), 6.78
(d, J=8.4 Hz, 2H), 7.04-7.18 (m, 6H), 7.28 (app.t, J=8.4 Hz, 2H),
7.32 (s, 1H).
[0434] m/z 558.3 (M+H).
EXAMPLE 35
2-(3-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihy-
droxy-tetrahydro-pyran-2-ylmethanesulfonyl}-phenyl)-acetamide
##STR00050##
[0436] Title compound was prepared according to the procedure as
described in example 3.
[0437] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.34 (t, J=7.2
Hz, 3H), 3.04 (t, J=9.2 Hz, 1H), 3.12-3.16 (m, 1H), 3.20 (d, J=11.2
Hz, 1H), 3.37 (t, J=8.8 Hz, 2H), 3.47-3.53 (m, 2H), 3.63 (d, J=14.0
Hz, 1H), 3.74 (t, J=9.6 Hz, 1H), 3.86 (t, J=9.2 Hz, 1H), 3.96 (q,
J=7.2 Hz, 2H), 4.05 (d, J=14.8 Hz, 1H), 6.78-6.82 (m, 3H), 6.95 (d,
J=2.0 Hz, 1H), 7.03 (app. t, J=8.0 Hz, 1H), 7.10 (d, J=8.8 Hz, 2H),
7.21 (app. t, J=8.0 Hz, 2H), 7.56 (d, J=7.6 Hz, 1H), 7.68 (s,
1H).
[0438] MS (ES) m/z 590.3 (M+H).
EXAMPLE 36
(3-{(2S,3S,4R,6R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-4-fluoro-phenyl)-pyrrolidin-1-yl--
methanone
##STR00051##
[0440] Title compound was prepared according to the procedure as
described in example 3.
[0441] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.38 (t, J=7.2
Hz, 3H), 1.73-1.78 (m, 2H), 1.87-1.92 (m, 2H), 3.18-3.30 (m, 4H),
3.44 (t, J=8.8 Hz, 1H), 3.48-3.61 (m, 5H), 3.93-4.06 (m, 5H), 6.81
(d, J=8.8 Hz, 2H), 7.04 (d, J=8.4 Hz, 1H), 7.09 (d, J=8.8 Hz, 3H),
7.15 (s, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.31-7.35 (m, 1H), 7.72 (dd,
J=1.6 7.0 Hz, 1H).
[0442] MS (ES) m/z 616.1 (M+H).
EXAMPLE 37
Azetidin-1-yl-(3-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-
-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethylsulfanyl}-4-fluoro-phenyl)-me-
thanone
##STR00052##
[0444] Title compound was prepared according to the procedure as
described in example 3.
[0445] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.37 (t, J=7.2
Hz, 3H), 1.77-2.26 (m, 2H), 3.20-3.26 (m, 2H), 3.42-3.52 (m, 3H),
3.60-3.63 (m, 1H), 3.92-4.23 (m, 9H), 6.80 (d, J=8.8 Hz, 2H),
7.03-7.09 (m, 4H), 7.13 (s, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.43-7.47
(m, 1H), 7.80 (dd, J=1.6 7.6 Hz, 1H).
[0446] MS (ES) m/z 602.0 (M+H).
EXAMPLE 38
2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5
trihydroxytetrahydro-pyran-2 ylmethylsulfanyl}-N-methyl
benzamide
##STR00053##
[0448] Title compound was prepared according to the procedure as
described in example 3.
[0449] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.35 (t, J=7.2
Hz, 3H), 2.79 (s, 3H), 3.10 (dd, J=7.6, 13.6 Hz, 1H), 3.32-3.43 (m,
1H), 3.48-3.55 (m, 4H), 3.96-4.07 (m, 5H), 7.58 (d, J=7.6 Hz, 2H),
7.09 (d, J=10.4 Hz, 2H), 7.14-7.23 (m, 3H), 7.27-7.35 (m, 3H), 7.58
(d, J=7.6 Hz, 1H).
[0450] m/z 558.0 (M+H)
EXAMPLE 39
2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydro-
xy-tetrahydro-pyran-2-ylmethylsulfanyl}-N-ethyl-benzamide
##STR00054##
[0452] Title compound was prepared according to the procedure as
described in example 3.
[0453] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.16 (t, J=7.6
Hz, 3H), 1.36 (t, J=7.2 Hz, 3H), 3.10 (dd, J=7.2, 13.6 Hz, 1H),
3.24-3.27 (m, 3H), 3.41-3.43 (m, 2H), 3.44-3.54 (m, 2H), 3.96-4.07
(m, 5H), 6.81 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz 2H), 7.13-7.22
(m, 3H), 7.27-7.33 (m, 3H), 7.58 (d, J=8.0 Hz, 1H).
[0454] m/z 572.1 (M+H).
EXAMPLE 40
3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydro-
xy-tetrahydro-pyran-2-ylmethylsulfanyl}-N-methyl-benzamide
##STR00055##
[0456] Title compound was prepared according to the procedure as
described in example 3.
[0457] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.36 (t, J=7.2
Hz, 3H), 2.87 (s, 3H), 3.18-3.23 (m, 2H), 3.33-3.60 (m, 4H),
3.91-4.06 (m, 5H), 6.80 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.4 Hz, 3H),
7.14 (s, 1H), 7.26-7.30 (m, 2H), 7.55 (d, J=8.0 Hz, 2H), 7.85 (s,
1H). MS (ES) m/z 558.1 (M+H).
EXAMPLE 41
3-{(2S,3S,4R,5R,6S)-6-[4Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydrox-
y-tetrahydro-pyran-2-ylmethylsulfanyl}-N-ethyl-benzamide
##STR00056##
[0459] Title compound was prepared according to the procedure as
described in example 3.
[0460] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.19 (t, J=7.2
Hz, 3H), 1.36 (t, J=7.2 Hz, 3H), 3.18-3.23 (m, 2H), 3.33-3.60 (m,
7H), 3.91-4.07 (m, 4H), 6.80 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.4 Hz,
3H), 7.15 (d, J=1.6 Hz, 1H), 7.26-7.30 (m, 2H), 7.55 (t, J=8.0,
2H), 7.85 (s, 1H).
[0461] MS (ES) m/z 572.1 (M+H).
EXAMPLE 42
4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydro-
xy-tetrahydro-pyran2ylmethylsulfanyl}-N-methyl-benzamide
##STR00057##
[0463] Title compound was prepared according to the procedure as
described in example 3.
[0464] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.37 (t, J=6.8
Hz, 3H), 2.92 (s, 3H), 3.22 (t, J=8.4 Hz, 2H), 3.47 (qui, J=8.8 Hz,
2H), 3.57 (br d, J=14.5 Hz, 2H), 3.91-4.07 (m, 5H), 6.79 (d, J=8.0
Hz, 2H), 7.06 (d, J=8.0 Hz, 3H), 7.16 (s, 1H), 7.27 (d, J=8.0 Hz,
1H), 7.44 (d, J=8.0 Hz, 2H), 7.67 (d, J=8.0 Hz, 2H).
[0465] MS (ES) m/z 558.1 (M+H).
EXAMPLE 43
4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydro-
xy-tetrahydro-pyran2ylmethylsulfanyl}-N-ethyl-benzamide
##STR00058##
[0467] Title compound was prepared according to the procedure as
described in example 3.
[0468] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.32 (t, J=7.0
Hz, 3H), 1.37 (t, J=6.8 Hz, 3H), 3.17-3.23 (m, 2H), 3.84-3.52 (m,
5H), 3.57-3.62 (m, 2H), 3.90-4.07 (m, 4H), 6.79 (d, J=8.0 Hz, 2H),
7.03-7.07 (m, 3H), 7.15 (d, J=0.8 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H),
7.44 (d, J=8.0 Hz, 2H), 7.68 (d, J=8.0 Hz, 2H).
[0469] MS (ES) m/z 572.1 (M+H).
EXAMPLE 44
4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydro-
xy-tetrahydro-pyran2ylmethylsulfanyl}-N-ethyl-benzamide
##STR00059##
[0471] Title compound was prepared according to the procedure as
described in example 3.
[0472] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.17-1.19 (m,
6H), 1.37 (t, J=7.2 Hz, 3H), 3.11 (dd, J=7.2, 13.6 Hz, 1H),
3.22-3.32 (m, 1H), 3.42-3.55 (m, 4H), 3.96-4.13 (m, 6H), 6.81 (d,
J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H), 7.13-7.22 (m, 3H), 7.26-7.32
(m, 3H), 7.58 (d, J=8.0 Hz, 1H).
[0473] m/z 586.1 (M+H).
EXAMPLE 45
(2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-pyrrolidin-1
yl-methanone
##STR00060##
[0475] Title compound was prepared according to the procedure as
described in example 3.
[0476] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.37 (t, J=6.8
Hz, 3H), 1.65-1.72 (m, 2H), 1.80-1.86 (m, 2H), 2.99-3.02 (m, 2H),
3.13-3.21 (m, 2H), 3.39-3.44 (m, 2H), 3.49-3.58 (m, 4H), 3.91-4.07
(m, 5H), 6.81 (d, J=8.8 Hz, 2H), 7.07 (br d, J=8.4 Hz, 3H), 7.15
(br d, J=5.6 Hz, 2H), 7.22 (t, J=6.8 Hz, 1H), 7.29 (d, J=8.0 Hz,
2H), 7.59 (d, J=8 Hz, 1H).
[0477] MS (ES) m/z 598.1 (M+H).
EXAMPLE 46
3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydro-
xy-tetrahydro-pyran-2-ylmethylsulfanyl}-N-isopropyl-benzamide
##STR00061##
[0479] Title compound was prepared according to the procedure as
described in example 3.
[0480] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.21-1.26 (m,
6H), 1.38 (t, J=7.2 Hz, 3H), 3.19-3.24 (m, 2H), 3.43-3.61 (m, 4H),
3.93-4.08 (m, 5H), 4.18-4.21 (m, 1H), 6.80 (d, J=8.4 Hz, 2H), 7.07
(d, J=8.4 Hz, 2H), 7.17 (s, 1H), 7.27-7.30 (m, 3H), 7.56 (t, J=8.4,
2H), 7.86 (s, 1H).
[0481] MS (ES) m/z 586.1 (M+H).
EXAMPLE 47
(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-pyrrolidin-1
yl-methanone
##STR00062##
[0483] Title compound was prepared according to the procedure as
described in example 3.
[0484] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.38 (t, J=6.8
Hz, 3H), 1.79-1.91 (m, 2H), 1.89-1.94 (m, 2H), 3.19-3.30 (m, 4H),
3.47 (t, J=8.8 Hz 1H), 3.51-3.60 (m, 5H), 3.94-4.03 (m, 4H), 4.07
(d, J=9.6 Hz, 1H), 6.81 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H),
7.18 (d, J=1.2 Hz, 1H), 7.26-7.33 (d, 3H), 7.51 (d, J=8.8 Hz, 2H),
7.58 (s, 1H).
[0485] MS (ES) m/z 598.1 (M+H).
EXAMPLE 48
4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydro-
xy-tetrahydro-pyran-2-ylmethylsulfanyl}-N-isopropyl-benzamide
##STR00063##
[0487] Title compound was prepared according to the procedure as
described in example 3.
[0488] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.26 (d, J=6.4
Hz, 3H), 1.27 (d, J=6.4 Hz, 3H), 1.37 (t, J=7.2 Hz, 3H), 3.18-3.24
(m, 2H), 3.43-3.54 (m, 2H), 3.59-3.62 (m, 2H), 3.91-4.08 (m, 5H),
4.22 (qui, J=6.4 Hz, 1H), 6.80 (d, J=8.0 Hz, 2H), 7.04-7.09 (m,
3H), 7.17 (br s, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.45 (d, J=8.0 Hz,
2H), 7.60 (d, J=8.0 Hz, 2H).
[0489] MS (ES) m/z 586.1 (M+H).
EXAMPLE 49
(4-{(2S,3S,4R,5R,6S)-6-[4Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydro-
xy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-pyrrolidin-1
yl-methanone
##STR00064##
[0491] Title compound was prepared according to the procedure as
described in example 3.
[0492] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.38 (t, J=6.8
Hz, 3H), 1.86-1.90 (m, 2H), 1.95-2.00 (m, 2H), 3.18-3.28 (m, 2H),
3.37-3.52 (m, 4H), 3.56-3.64 m, 4H), 3.96-4.09 (m, 5H), 6.81 (d,
J=8.4 Hz, 2H), 7.09-7.14 (m, 3H), 7.24 (br s, 1H), 7.31 (d, J=8.0
Hz, 1H), 7.37 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H).
[0493] MS (ES) m/z 598.1
EXAMPLE 50
3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydro-
xy-tetrahydro-pyran-2-ylmethylsulfanyl}-N,N-dimethyl-benzamide
##STR00065##
[0495] Title compound was prepared according to the procedure as
described in example 3.
[0496] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.38 (t, J=7.2
Hz, 3H), 2.83 (s, 3H), 3.04 (s, 3H), 3.18-3.33 (m, 2H), 3.44-3.53
(m, 3H), 3.56-3.60 (m, 1H), 3.95-4.08 (m, 5H), 6.81 (d, J=8.4 Hz,
2H), 7.09-7.12 (m, 3H), 7.16 (d, J=7.6 Hz, 1H), 7.2 (d, J=1.6 Hz
1H), 7.3 (m, 2H), 7.45 (s, 1H) 7.50 (d, J=8.0, 1H).
[0497] MS (ES) m/z 572.1 (M+H).
EXAMPLE 51
4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)phenyl]-3,4,5-trihydrox-
y-tetrahydro-pyran-2-ylmethylsulfanyl}-N,N-dimethyl-benzamide
##STR00066##
[0499] Title compound was prepared according to the procedure as
described in example 3.
[0500] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.38 (t, J=6.8
Hz, 3H), 2.95 (s, 3H), 2.09 (s, 3H), 3.21-3.26 (m, 2H), 3.45-3.49
(m, 2H), 3.55-3.61 (m, 2H), 3.98-4.09 (m, 5H), 6.82 (d, J=8.0 Hz,
2H), 7.07 (m, 3H), 7.24 (br s, 1H), 7.27 (d, J=8.0 Hz, 2H), 7.32
(d, J=8.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 2H).
[0501] MS (ES) m/z 572.1 (M+H).
EXAMPLE 52
2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydro-
xy-tetrahydro-pyran-2-ylmethylsulfanyl}-N,N-dimethyl-benzamide
##STR00067##
[0503] Title compound was prepared according to the procedure as
described in example 3.
[0504] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.38 (t, J=6.8
Hz, 3H), 2.7 (s, 3H), 3.03 (s, 3H), 3.15-3.26 (m, 2H), 3.42-3.44
(m, 2H), 3.52-3.55 (m, 2H), 3.95-4.08 (m, 5H), 6.82 (d, J=8.4 Hz,
2H), 7.08-7.18 (m, 5H), 7.21-7.32 (m, 3H), 7.60 (d, J=8.0 Hz,
1H).
[0505] m/z 572.0(M+H)
EXAMPLE 53
4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydro-
xy-tetrahydro-pyran-2-ylmethylsulfanyl}-benzamide
##STR00068##
[0507] Title compound was prepared according to the procedure as
described in example 3.
[0508] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.38 (t, J=7.0
Hz, 3H), 3.19-3.25 (m, 2H), 3.34-3.50 (m, 2H), 3.53-3.64 (m, 2H),
3.96-4.09 (m, 5H), 6.80 (d, J=8.0 Hz, 2H), 7.07 (d, J=8.0 Hz, 3H),
7.18 (d, J=1.2 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.45 (d, J=8.0 Hz,
2H), 7.75 (d, J=8.0 Hz, 2H).
[0509] MS (ES) ink 544.1 (M+H).
EXAMPLE 54
Cyclopentanecarboxylic acid
(3-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-amide
##STR00069##
[0511] Title compound was prepared according to the procedure as
described in example 25.
[0512] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.37 (t, J=6.8
Hz, 3H), 1.64 (m, 2H), 1.78 (m, 4H), 1.90 (m, 2H), 2.76 (m, 1H),
3.13-3.22 (m, 2H), 3.33-3.60 (m, 4H), 3.91-4.08 (m, 5H), 6.80 (d,
J=8.4 Hz, 2H), 7.061 (m, 6H), 7.27 (d, J=8.0 Hz, 1H), 7.61 (d,
J=8.0 Hz, 1H), 7.68 (s, 1H).
[0513] MS (ES) m/z 613.1 (M+2).
EXAMPLE 55
N-(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,6-trihy-
droxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-benzamide
##STR00070##
[0515] Title compound was prepared according to the procedure as
described in example 25.
[0516] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.36 (t, J=7.2
Hz, 3H), 3.16-3.25 (m, 2H), 3.33-3.62 (m, 4H), 3.90-4.09 (m, 5H),
6.78 (d, J=7.2 Hz, 2H), 7.05 (d, J=8.8 Hz, 2H), 7.09-7.11 (dd,
J=1.6, 8.0 Hz, 1H), 7.18-7.28 (m, 4H), 7.52 (d, J=8.0 Hz, 3H), 7.60
(t, J=7.2 Hz, 1H), 7.83 (s, 1H), 7.89 (d, J=7.2 Hz, 2H).
[0517] MS (ES) m/z 620.1 (M+2).
EXAMPLE 56
Cyclohexanecarboxylic acid
(3-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2ylmethylsulfanyl}-phenyl)-amide
##STR00071##
[0519] Title compound was prepared according to the procedure as
described in example 25.
[0520] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.29-1.04 (m,
5H), 1.48-1.52 (m, 2H), 1.73 (br d, J=12.0 Hz, 2H), 1.83 (br d,
J=12.0 Hz, 4H), 2.30-2.33 (m, 1H), 3.14-3.22 (m, 2H), 3.45 (t,
J=8.8 Hz, 1H), 3.51-3.55 (m, 2H), 3.58-3.60 (m, 1H), 3.91-4.08 (m,
5H), 6.80 (d, J=8.4 Hz, 2H), 7.06 (d, J=8.4 Hz, 3H), 7.11-7.17 (m,
3H), 7.28 (d, J=8.0 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.68 (br s,
1H).
[0521] MS (ES) m/z 627.2 (M+2)
EXAMPLE 57
N-(2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihy-
droxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-benzamide
##STR00072##
[0523] Title compound was prepared according to the procedure as
described in example 25.
[0524] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.36 (t, J=7.2
Hz, 3H), 2.97-2.99 (m, 1H), 3.14-3.16 (m, 2H), 3.52 (d, J=13.6 Hz,
2H), 3.86-3.90 (m, 4H), 3.97 (q, J=6.8 Hz, 2H), 6.78 (d, J=8.8 Hz,
2H), 6.97-7.04 (m, 4H), 7.15-7.18 (m, 2H), 7.35 (t, J=7.6 Hz, 3H),
7.54 (t, J=7.6 Hz, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.81 (d, J=7.2 Hz,
2H), 8.12 (d, 8.0 Hz, 1H).
[0525] MS (ES) m/z 620.1
EXAMPLE 58
N-(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihy-
droxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-benzamide
##STR00073##
[0527] Title compound was prepared according to the procedure as
described in example 25.
[0528] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.29 (t, J=6.8
Hz, 3H), 3.01-3.11 (m, 2H), 3.27 (br s, 2H), 3.41-3.47 (m, 2H),
3.91-4.04 (m, 5H), 4.93 (d, J=5.6 Hz, 1H), 5.07 (d, J=4.0 Hz, 1H),
5.27 (d, J=4.0 Hz, 1H), 6.82 (d, J=8.8 Hz, 2H), 7.09 (d, J=8.8 Hz,
2H), 7.13 (s, 1H), 7.24 (s, 1H), 7.34-7.37 (m, 3H), 7.53-7.61 (m,
3H), 7.72 (d, J=8.8 Hz, 2H), 7.94 (d, J=8.0 Hz, 2H), 10.28 (s,
1H).
[0529] MS (ES) m/z 620.0 (M+H).
EXAMPLE 59
Cyclohexanecarboxylic acid
(4-{(2S,3S,4R,5R,6S)-6-[4-chloro3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-amide
##STR00074##
[0531] Title compound was prepared according to the procedure as
described in example 25.
[0532] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.32-1.40 (m,
6H), 1.53-1.56 (m, 2H), 1.76 (br d, J=12.0 Hz, 1H), 1.88 (br t,
J=13.6 Hz, 4H), 2.35-2.38 (m, 1H), 3.11 (dd, J=6.4, 14.0, Hz, 1H),
3.20 (t, J=9.2 Hz, 1H), 3.41-3.55 (m, 4H), 3.93-4.06 (m, 5H), 6.81
(d, J=8.4 Hz, 2H), 7.02 (dd, J=1.6, 8.4 Hz, 1H), 7.08 (d, J=8.4 Hz,
2H), 7.16 (s, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.36 (d, J=8.8 Hz, 2H),
7.46 (d, J=8.8 Hz, 2H). MS (ES) m/z 626.1,
EXAMPLE 60
Cyclopentanecarboxylic acid
(4-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxybenzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-amide
##STR00075##
[0534] Title compound was prepared according to the procedure as
described in example 25.
[0535] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.37 (t, J=7.2
Hz, 3H), 1.67 (br s, 2H), 1.81-1.87 (m, 4H), 1.96 (br s, 2H), 2.8
(dd, J=6.8, 14.4 Hz, 1H), 3.18 (t, J=8.8 Hz, 2H), 3.41-3.55 (m,
4H), 3.93-4.06 (m, 5H), 6.81 (d, J=8.4 Hz, 2H), 7.03 (dd, J=2.0,
8.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 2H), 7.16 (s, 1H), 7.28 (d, J=8.4
Hz, 1H), 7.37 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H).
[0536] MS (ES) m/z 612.1
EXAMPLE 61
N-(4-{(2S,3S,4R,6R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,6-trihy-
droxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-acetamide
##STR00076##
[0538] Title compound was prepared according to the procedure as
described in example 25.
[0539] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.38 (t, J=6.8
Hz, 3H), 2.13 (s, 3H), 3.08 (dd, J=6.8 & 14.4, Hz, 1H), 3.21
(t, J=9.2 Hz, 1H), 3.41-3.57 (m, 4H), 3.95-4.07 (m, 5H), 6.81 (d,
J=8.8 Hz, 2H), 7.07-7.09 (m, 3H), 7.17 (s, 1H), 7.30 (d, J=8.0 Hz,
1H), 7.36 (d, J=9.2 Hz, 2H), 7.43 (d, J=8.8 Hz, 2H). MS (ES) m/z
558.0 (M+H).
EXAMPLE 62
N-(2-{(2S,3S,4R5R6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-acetamide
##STR00077##
[0541] Title compound was prepared according to the procedure as
described in example 25.
[0542] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.30 (t, J=6.8
Hz, 3H), 1.97 (s, 3H), 2.97 (dd, J=8.0, 13.2 Hz, 1H), 3.10-3.13 (m,
1H), 3.22-3.27 (m, 3H), 3.41-3.43 (m, 1H), 3.92-4.04 (m, 5H), 4.95
(d, J=5.6 Hz, 1H), 5.11 (d, J=4.8 Hz, 1H), 5.33 (d, J=4.8 Hz, 1H),
6.83 (d, J=8.8 Hz, 2H), 7.09-7.12 (m, 3H), 7.13-7.19 (m, 2H), 7.27
(d, J=1.6 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.45 (dd, J=1.2 &
7.6 Hz, 1H), 7.51-7.53 (d, J=7.6 Hz, 1H), 9.21 (s, 1H).
[0543] m/z 558.0(M+H)
EXAMPLE 63
Cyclohexanecarboxylic acid
(2-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-amide
##STR00078##
[0545] Title compound was prepared according to the procedure as
described in example 25.
[0546] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.16-1.24 (m,
4H), 1.28-1.36 (m, 5H), 1.59 (d, J=10 Hz, 1H), 1.68 (d, J=8.0 Hz,
2H), 1.78 (d, J=12.8 Hz, 2H), 2.26-2.25 (m, 1H), 2.96 (dd, J=8.4,
13.6 Hz, 1H), 3.08-3.09 (m, 1H), 3.17-3.26 (m, 2H), 3.31-3.42 (m,
1H), 3.85-4.05 (m, 5H), 4.94 (d, J=6.0 Hz, 1H), 5.15 (d, J=4.4 Hz,
1H), 5.31 (d, J=4.8 Hz, 1H), 6.82 (d, J=8.8 Hz, 2H), 7.09 (d, J=8.4
Hz, 3H), 7.15-7.19 (m, 2H), 7.26 (s, 1H), 7.36 (d, J=8.4 Hz, 1H),
7.47 (d, J=7.6 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 9.03 (s, 1H).
[0547] m/z 626.2(M+H)
EXAMPLE 64
Cyclopentanecarboxylic acid
(2-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-amide
##STR00079##
[0549] Title compound was prepared according to the procedure as
described in example 25.
[0550] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.29 (t, J=7.2
Hz, 3H), 1.41-1.49 (m, 2H), 1.55-1.82 (m, 6H), 2.64-2.75 (m, 1H),
2.96 (dd, J=8.4, 13.6 Hz, 1H), 3.09 (q, J=2.4 Hz, 1H), 3.21-3.26
(m, 2H), 3.31-3.42 (m, 2H), 3.92-4.03 (m, 5H), 4.94 (d, J=6 Hz,
1H), 5.15 (d, J=4.4 Hz, 1H), 5.31 (d, J=4.8 Hz, 1H), 6.82 (d, J=8.4
Hz, 2H), 7.09 (d, J=8 Hz, 3H), 7.15-7.20 (m, 2H), 7.26 (s, 1H),
7.36 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.0 Hz,
1H), 9.06 (s, 1H).
[0551] m/z 612.1(M+H)
EXAMPLE 65
Cyclopropanecarboxylic acid
(2-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-amide
##STR00080##
[0553] Title compound was prepared according to the procedure as
described in example 25.
[0554] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 0.70-0.76 (m,
4H), 1.35 (t, J=6.8 Hz, 3H), 1.72-1.82 (m, 1H), 3.00 (dd, J=7.2,
13.6 Hz, 1H), 3.10-3.16 (m, 1H), 3.25-3.29 (m, 3H), 3.42-3.49 (m,
1H), 3.93-4.06 (m, 5H), 4.95 (d, J=5.2 Hz, 1H), 5.11 (br s, 1H),
5.33 (br s, 1H), 6.83 (d, J=8.0 Hz, 2H), 7.09-7.19 (m, 5H), 7.28
(s, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.46-7.53 (m, 2H), 9.42 (s,
1H).
[0555] m/z 584.0(M+H)
EXAMPLE 66
Cyclopropanecarboxylic acid
(3-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,6-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-amide
##STR00081##
[0557] Title compound was prepared according to the procedure as
described in example 25.
[0558] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 0.78-0.80 (m,
4H), 1.30 (t, J=7.2 Hz, 3H), 1.74-1.77 (m, 1H), 3.02-3.09 (m, 2H),
3.26-3.28 (m, 2H), 3.41-3.49 (m, 2H), 3.90-4.05 (m, 5H), 4.95 (d,
J=6.0 Hz, 1H), 5.09 (d, J=4.4 Hz, 1H), 5.29 (d, J=4.8 Hz, 1H), 6.29
(d, J=8.4 Hz, 2H), 7.01 (d, J=7.6 Hz, 1H), 7.08-7.20 (m, 4H), 7.245
(s, 1H), 7.35 (d, J=8.4 Hz, 2H), 7.63 (s, 1H), 10.21 (s, 1H).
[0559] MS (ES) m/z 584.0 (M+H).
EXAMPLE 67
N-(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihy-
droxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-propionamide
##STR00082##
[0561] Title compound was prepared according to the procedure as
described in example 25.
[0562] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.07 (t, J=7.2
Hz, 3H), 1.30 (t, J=7.2 Hz, 3H), 2.27-2.33 (m, 2H), 3.02-3.10 (m,
2H), 3.26-3.28 (m, 2H), 3.41-3.49 (m, 2H), 3.91-4.05 (m, 5H), 4.94
(d, J=6.0 Hz, 1H), 5.08 (d, J=4.4 Hz, 1H), 5.28 (d, J=4.8 Hz, 1H),
6.83 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.0 Hz, 1H), 7.08-7.20 (m, 4H),
7.25 (s, 1H), 7.36 (t, J=8.4 Hz, 2H), 7.63 (s, 1H), 9.86 (s,
[0563] MS (ES) m/z 572.0 (M+H).
EXAMPLE 68
(2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-carbamic acid
methyl ester
##STR00083##
[0565] Title compound was prepared according to the procedure as
described in example 25.
[0566] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.30 (t, J=6.8
Hz, 3H), 2.96 (dd, J=8.0, 13.6 Hz, 1H), 3.11 (q, J=5.2 Hz, 1H),
3.21-3.26 (m, 2H), 3.31-3.40 (m, 2H), 3.57 (s, 3'-1) 3.93-4.03 (m,
5H), 4.95 (d, J=6.0 Hz, 1H), 5.11 (d, J=4.4 Hz, 1H), 5.31 (d, J=4.8
Hz, 1H), 6.83 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.8 Hz, 3H), 7.15-7.20
(m, 2H), 7.26 (s, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.46-7.49 (m, 2H),
8.59 (s, 1H).
[0567] m/z 574.0(M+H)
EXAMPLE 69
(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,6-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-carbamic acid
methyl ester
##STR00084##
[0569] Title compound was prepared according to the procedure as
described in example 25.
[0570] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.30 (t, J=7.2
Hz, 3H), 3.02-3.12 (m, 2H), 3.25-3.28 (m, 2H), 3.41-3.49 (m, 2H),
3.66 (s, 3H), 3.91-4.05 (m, 5H), 4.95 (d, J=5.6 Hz, 1H), 5.10 (d,
J=4.0 Hz, 1H), 5.30 (d, J=4.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 2H), 6.97
(d, J=8.0 Hz, 1H), 7.08-7.20 (m, 4H), 7.25 (d, J=1.6 Hz, 2H), 7.35
(d, J=8.0 Hz, 1H) 7.46 (s, 1H) 9.67 (s, 1H).
[0571] MS (ES) m/z 574.0 (M+H).
EXAMPLE 70
N-(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihy-
droxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-propionamide
##STR00085##
[0573] Title compound was prepared according to the procedure as
described in example 25.
[0574] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.09 (t, J=7.2
Hz, 3H), 1.31 (t, J=6.8 Hz, 3H), 2.31 (q, J=7.2 Hz, 2H), 3.01 (dd,
J=7.2 & 14.4, Hz, 1H), 3.09 (t, J=9.2 Hz, 1H), 3.26 (br d,
J=3.6 Hz, 2H), 3.39-3.45 (m, 2H), 3.91-4.03 (m, 5H), 4.93 (d, J=6.0
Hz, 1H), 5.07 (d, J=3.6 Hz, 1H), 5.27 (d, J=4.4 Hz, 1H), 6.83 (d,
J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H), 7.24 (s, 1H), 7.28 (d, J=8.4
Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.8 Hz, 2H), 9.89 (s,
1H). MS (ES) m/z 572.0 (M+H).
EXAMPLE 71
(4-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-carbamicacid
methyl ester
##STR00086##
[0576] Title compound was prepared according to the procedure as
described in example 25.
[0577] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.31 (t, J=6.8
Hz, 3H), 2.99 (dd, J=, 7.2 & 14.4 Hz, 1H), 3.09 (t, J=9.2 Hz,
1H), 3.26 (br s, 2H), 3.81-3.40 (m, 2H), 3.67 (s, 3H), 3.95-4.03
(m, 5H), 4.93 (d, J=6.4 Hz, 1H), 5.07 (d, J=4.4 Hz, 1H), 5.26 (d,
J=4.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 2H), 7.08-7.12 (m, 3H), 7.24 (s,
1H), 7.28 (d, J=8.4 Hz, 2H), 7.34-7.4 (m, 3H), 9.69 (s, 1H).
[0578] MS (ES) m/z 574.0 (M+H).
EXAMPLE 72
N-(2-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihy-
droxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-propionamide
##STR00087##
[0580] Title compound was prepared according to the procedure as
described in example 25.
[0581] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 1.00 (t, J=6.0
Hz, 3H), 1.22 (t, J=6.8 Hz, 3H), 2.19-2.24 (m, 2H), 2.95 (dd,
J=8.0, 13.6 Hz, 1H), 3.05-3.14 (m, 1H), 3.20-3.25 (m, 2H),
3.30-3.42 (m, 2H), 3.91-4.02 (m, 6H), 4.92 (d, J=6.0 Hz, 1H), 5.10
(d, J=4.4 Hz, 1H), 5.31 (d, J=5.2 Hz, 1H), 6.81 (d, J=8.4 Hz, 2H),
7.08 (d, J=8.8 Hz, 2H), 7.14-7.19 (m, 2H), 7.25 (s, 1H), 7.36 (d,
J=8.4 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.55 (d, J=7.6 Hz, 1H), 9.09
(s, 1H). m/z 572.0(M+H)
EXAMPLE 73
Cyclopropanecarboxylic acid
(4-{(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihyd-
roxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-amide
##STR00088##
[0583] Title compound was prepared according to the procedure as
described in example 25.
[0584] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 0.87-0.89 (m,
2H), 0.98 (t, J=4.0 Hz, 2H), 1.37 (t, J=7.2 Hz, 3H), 1.71 (br s,
1H), 3.13 (dd, J=6.8, 14.4, Hz, 1H), 3.21 (t, J=9.2 Hz, 1H),
3.41-3.55 (m, 4H), 3.98-4.07 (m, 5H), 6.81 (d, J=8.0 Hz, 2H), 7.05
(s, 1H), 7.08 (d, J=8.4 Hz, 2H), 7.16 (s, 1H), 7.30 (d, J=8.4 Hz,
1H), 7.36 (d, J=8.8 Hz, 2H), 7.45 (d, J=8.8 Hz, 2H). MS (ES) m/z
584.0
EXAMPLE 74
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-[4-(2-hydroxy
ethyl)benzenesulfonylmethyl]-tetrahydro-pyran-3,4,5-triol
##STR00089##
[0586] Title compound was prepared according to the procedure as
described in example 5.
[0587] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.35 (t, J=6.8
Hz, 3H), 2.53-2.58 (m, 2H), 3.08-3.17 (m, 2H), 3.38 (t, J=9.2 Hz,
2H), 3.44 (d, J=4.8 Hz, 1H), 3.58 (t, J=6.8 Hz, 2H), 3.75 (t,
J=10.8 Hz, 1H), 3.84 (d, J=9.6 Hz, 1H), 3.90-4.07 (m, 5H),
6.80-6.84 (m, 3H), 6.94 (d, J=8.4 Hz, 2H), 7.01 (d, J=1.6 Hz, 1H),
7.14 (d, J=8.8 Hz, 2H), 7.22 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.0 Hz,
1H).
[0588] MS (ES) m/z 577.3 (M+H).
EXAMPLE 75
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-[3-(2-hydroxy-e-
thyl)benzenesulfonylmethyl]-tetrahydro-pyran-3,4,5-triol
##STR00090##
[0590] Title compound was prepared according to the procedure as
described in example 5.
[0591] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.35 (t, J=7.2
Hz, 3H), 2.47-2.53 (m, 2H), 3.07 (t, J=9.2 Hz, 1H), 3.14 (t, J=9.6
Hz, 1H), 3.36 (t, J=8.8 Hz, 1H), 3.49-3.52 (m, 1H), 3.56 (t, J=6.8
Hz, 2H), 3.62 (d, J=14 Hz, 1H), 3.74 (t, J=9.6 Hz, 1H),3.82 (s,
1H), 3.85 (d, J=6.8 Hz, 1H), 3.98 (q, J=6.8 Hz, 2H), 4.04 (d,
J=15.2 Hz, 1H), 6.80 (d, J=8.8 Hz, 3H), 6.92 (d, J=1.6 Hz, 1H),
7.07-7.10 (m, 3H), 7.14 (d, J=8.0 Hz, 1H), 7.21 (d, J=8.40 Hz, 1H),
7.55 (d, J=6.4 Hz, 2H).
[0592] MS (ES) m/z 577.3 (M+H).
EXAMPLE 76
(2S,3R,4R,6S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-[3-(2-hydroxy-e-
thyl)phenylsulfanylmethyl]-tetrahydro-pyran-3,4,5-triol
##STR00091##
[0594] Title compound was prepared according to the procedure as
described in example 5.
[0595] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.34 (t, J=6.8
Hz, 3H), 2.69 (t, J=7.2 Hz, 2H), 3.06 (dd, J=6.8 Hz, J=14 Hz, 1H),
3.20 (t, J=9.2 Hz, 1H), 3.30-3.53 (m, 4H), 3.66 (t, J=6.8 Hz, 2H),
3.92-4.04 (m, 5H), 6.78 (d, J=8.4 Hz, 2H), 6.98 (d, J=7.2 Hz, 1H),
7.04-7.13 (m, 4H), 7.17 (s, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.24 (s,
1H), 7.28 (d, J=8.0 Hz, 1H).
[0596] MS (ES) m/z 562.3 (M+18).
EXAMPLE 77
(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-(3-hydroxymethy-
l-phenylsulfanylmethyl)-tetrahydro-pyran-3,4,5-triol
##STR00092##
[0598] Title compound was prepared according to the procedure as
described in example 5.
[0599] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.37 (t, J=6.8
Hz, 3H), 3.13 (dd, J=14.0 Hz & 7.2 Hz, 1H), 3.25 (t, J=8.8 Hz,
3.44-3.57 (m, 4H), 3.96-4.04 (m, 4H), 4.07 (d, J=9.6 Hz, 1H), 4.51
(s, 2H), 6.82 (d, J=8.8 Hz, 2H), 7.09 (d, J=8.8 Hz, 2H), 7.13 (d,
J=8.0 Hz, 2H), 7.18-7.22 (m, 2H), 7.30-7.38 (m, 2H), 7.40 (s,
1H).
[0600] MS (ES+) m/z 548.3 (M+18).
EXAMPLE 78
3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydro-
xy-tetrahydro-pyran-2-ylmethylsulfanyl}-benzamide
##STR00093##
[0602] Title compound was prepared according to the procedure as
described in example 3.
[0603] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.37 (t, J=7.2
Hz, 3H), 3.18-3.25 (m, 2H), 3.42-3.60 (m, 4H), 3.94-4.07 (m, 5H),
6.81 (d, J=8.8 Hz, 2H), 7.07-7.10 (m, 3H), 7.17 (d, J=2.0 Hz, 1H),
7.27-7.31 (m, 2H), 7.57 (d, J=8.4 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H),
7.91 (s, 1H).
[0604] MS (ES+) m/z 544.3 (M+1).
EXAMPLE 79
3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydro-
xy-tetrahydro-pyran-2-ylmethanesulfonyl}-benzamide
##STR00094##
[0606] Title compound was prepared according to the procedure as
described in example 6.
[0607] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.38 (t, J=7.2
Hz, 3H), 3.07 (t, J=8.8 Hz, 1H), 3.17 (t, J=8.8 Hz, 1H), 3.40 (t,
J=8.8 Hz, 1H), 3.56-3.62 (m, 1H), 3.68-3.72 (m, 1H), 3.78-3.84 (m,
2H), 3.89-3.93 (m, 1H), 3.99-4.07 (m, 3H), 6.76 (d, J=8.4 Hz, 1H),
6.83-6.85 (m, 3H), 7.10-7.16 (m, 3H), 7.21 (d, J=8.0 Hz, 1H), 7.76
(d, J=8.0 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 8.28 (s, 1H).
[0608] MS (ES+) m/z 576.3(M+1).
EXAMPLE 80
N-(3-{(2S,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihy-
droxy-tetrahydro-pyran-2-ylmethylsulfanyl}-phenyl)-acetamide
##STR00095##
[0610] Title compound was prepared according to analogous procedure
as described in example 25.
[0611] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.33 (t, J=6.8
Hz, 3H), 2.05 (s, 3H), 3.12 (dd, J=14.0 Hz & 6.8 Hz, 1H), 3.18
(t, J=9.2 Hz, 1H), 3.39-3.57 (m, 4H), 3.89-3.98 (m, 4H), 4.03 (d,
J=9.2 Hz, 1H), 6.77 (d, J=8.4 Hz, 2H), 7.03-7.08 (m, 3H), 7.10-7.14
(m, 3H), 7.26 (d, J=8.0 Hz, 1H), 7.30-7.31 (m, 1H), 7.60 (s,
1H).
[0612] MS (ES+) m/z 558.3 (M+1).
EXAMPLE 81
N-(3-{(2R,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihy-
droxy-tetrahydro-pyran-2-ylmethoxy}-phenyl)-acetamide
##STR00096##
[0614] Step I. To a mixture of toluene-4-sulfonic acid
(2R,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydroxy-
-tetrahydro-pyran-2-ylmethyl ester (150 mg, 0.26 mmole) in
dimethylformamide (3 mL), 3-nitrophenol (74 mg, 0.53 mmole),
potassium carbonate (150 mg, 1.06 mmole) were added and stirred at
130.degree. C. for 12 hours. The reaction mixture was diluted with
water (25 mL) and extracted with dichloromethane (4.times.25 mL),
resulting organic layer washed with brine (25 mL).The product
obtained after the removal of solvent furnished
(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-(3-nitro-pheno-
xymethyl)-tetrahydro-pyran-3,4,5 triol (120 mg).
[0615] Step II. To a mixture of
(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-(3-nitro-pheno-
xymethyl)-tetrahydro-pyran-3,4,5-triol (120 mg, 0.22 mmole)
methanol (5 mL), Pd/C 10% on carbon (30 mg) was added and reaction
mixture was stirred under hydrogen atmosphere at room temperature
for 10 hours. The reaction mixture was filtered through celite bed,
filtrate was evaporated to furnish crude
2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-(3-amino-phenox-
ymethyl)-tetrahydro-pyran-3,4,5-triol (90 mg).
[0616] Step III. To a solution of
2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-(3-amino-phenox-
ymethyl)-tetrahydro-pyran-3,4,5-triol (90 mg, 1.8 mmole) in
pyridine (0.5 mL), acetic anhydride (0.1 mL), DMAP (1 mg) was added
at room temperature and stirred overnight. The reaction mixture was
diluted with water (10 mL) and acidified with 1N HCl, extracted
with dichloromethane (2.times.20 mL). The product obtained after
the removal of solvent furnished ccetic acid
(2R,3R,4R,5S,6S)-4,5-diacetoxy-2-(3-acetylamino-phenoxymethyl)-6-[4--
chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3-yl ester (150
mg).
[0617] Step IV. To a solution of acetic acid
(2R,3R,4R,5S,6S)-4,5-diacetoxy-2-(3-acetylamino-phenoxymethyl)-6-[4-chlor-
o-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3-yl ester (445 mg,
0.67 mmole) in THF: MeOH: H.sub.2O (3:1:2, 13 mL), lithium
hydroxide (56 mg, 1.33 mmole) was added at room temperature and
stirred overnight. The reaction mixture was diluted with water (10
mL) and extracted with ethyl acetate (3.times.20 mL). The crude
product obtained after the removal of solvent was purified using
preparative HPLC to furnish
N-(3-{(2R,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trih-
ydroxy-tetrahydro-pyran-2-ylmethoxy}-phenyl)-acetamide (14 mg).
[0618] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.37 (t, J=7.2
Hz, 3H), 2.11 (s, 3H), 3.28-3.30 (m, 1H), 3.50 (t, J=89.2 Hz, 1H),
3.59 (t, J=9.2 Hz, 1H), 3.65-3.71 (m, 1H), 3.96-4.03 (m, 4H), 4.15
(d, J=9.6 Hz, 1H), 4.20 (t, J=5.6 Hz, 1H), 4.34 (d, J=10 Hz, 1H),
6.73 (d, J=6.4 Hz, 1H), 6.80 (d, J=8.4 Hz, 2H), 7.06-7.10 (m, 3H),
7.18 (d, J=8.4 Hz, 1H), 7.23-7.28 (m, 2H), 7.32-7.35 (m, 2H). MS
(ES) m/z 542.2 (M+H).
EXAMPLE 82
3-{(2R,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydro-
xy-tetrahydro-pyran-2-ylmethoxy}-benzamide
##STR00097##
[0620] Step I. To a mixture of Toluene-4-sulfonic acid
(2R,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydroxy-
-tetrahydro-pyran-2-ylmethyl ester (700 mg, 1.24 mmole) in
dimethylformamide (3 mL), 3-hydroxymethylbenzoate (377 mg, 2.48
mmole), potassium carbonate (685 mg, 4.96 mmole) were added and
stirred at 130.degree. C. for 12 hrs. The reaction mixture was
diluted with water (25 mL) and extracted with dichloromethane
(4.times.25 mL), resulting organic layer washed with brine (25
mL).The product obtained after the removal of solvent furnished
3-{(2R,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethoxy}-benzoic acid methyl ester (350
mg).
[0621] Step II. To a mixture of
3-{(2R,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethoxy}-benzoic acid methyl ester (33 mg,
0.06 mmole) in THF:MeOH:H.sub.2O (3 mL), lithium hydroxide (4 mg,
0.12 mmole) was added at room temperature and stirred overnight.
The reaction mixture was diluted with water (10 mL) and neutralized
with 1N dilute HCl (0.2 mL) extracted with ethyl acetate
(3.times.20 mL). The crude product obtained after the removal of
solvent to furnish
3-{(2R,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-etrahydro-pyran-2-ylmethoxy}-benzoic acid (30 mg).
[0622] Step III. To a solution of
3-{(2R,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-etrahydro-pyran-2-ylmethoxy}-benzoic acid (100 mg, 0.18 mmole)
in DMF (1 mL), ammonia in tetrahydrofuran (1 mL), HOBt (30 mg, 0.22
mmole) was added and stirred for 10 minutes, EDCl (43 mg, 0.22
mmole) was added and stirred at room temperature overnight. The
reaction mixture was diluted with water (10 mL) and extracted with
ethyl acetate (2.times.20 mL) The crude product obtained after the
removal of solvent was purified using preparative HPLC to furnish
the title compound (21 mg).
[0623] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.37 (t, J=7.2
Hz, 3H), 3.29-3.31 (m, 1H), 3.52 (t, J=8.8 Hz, 1H), 3.61 (t, J=9.2
Hz, 1H), 3.73 (dd, J=4.0 & 9.6 Hz, 1H), 3.96-4.07 (m, 4H), 4.15
(d, J=10.4 Hz, 1H), 4.24 (dd, J=5.6 Hz, J=10.8 Hz, 1H), 4.42 (d,
J=9.6 Hz, 1H), 6.80 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H), 7.16
(dd, J=1.60 Hz, J=8.4 Hz, 1H), 7.23 (dd, J=2.0 Hz, J=8.0 Hz, 1H),
7.27 (s, 1H), 7.34-7.38 (m, 2H), 7.44-7.50 (m, 2H).
[0624] MS (ES) m/z 528.0 (M+H).
EXAMPLE 83
3-{(2R,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydro-
xy-tetrahydro-pyran-2-ylmethoxy}-N-methyl-benzamide
##STR00098##
[0626] To the solution of
3-{(2R,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethoxy}-benzoic acid methyl ester (100
mg, 0.18 mmole) in 2M methanolic methylammine (2.0 mL), 1,5,7
triazo bicycle[4,4,0] dec-5-ene (25 mg, 0.18 mmole) was added and
heated in sealed tube at 90.degree. C. for 24 hours. The reaction
mixture was concentrated and purified by preparative HPLC to
furnish the title compound (7 mg).
[0627] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.37 (t, J=7.2
Hz, 3H), 2.95 (s, 3H), 2.91-3.30 (m, 1H), 3.51 (t, J=9.2 Hz, 1H),
3.60 (t, J=9.2 Hz, 1H), 3.72 (dd, J=3.6 & 8.0 Hz, 1H),
3.96-4.07 (m, 4H), 4.15 (d, J=9.2 Hz, 1H), 4.25 (dd, J=5.2 &
10.8 Hz, 1H), 4.32 (d, J=10.8 Hz, 1H), 6.80 (d, J=8.4 Hz, 2H), 7.06
(d, J=8.4 Hz, 2H), 7.15 (d, J=8.0 Hz, 1H), 7.22-7.26 (m, 2H),
7.33-7.40 (m, 3H), 7.44 (s, 1H).
[0628] MS (ES) m/z 542.1 (M+H).
[0629] Examples 84 and 85 were prepared in an analogous procedure
as described in example
EXAMPLE 84
(3-{(2R,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydr-
oxy-tetrahydro-pyran-2-ylmethoxy}-phenyl)-pyrrolidin-1-yl-methanone
##STR00099##
[0631] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.38 (t, J=7.2
Hz, 3H), 1.87 (q, J=6.4 & 13.2 Hz, 2H), 1.95 (q, J=6.8 &
14.0 Hz, 2H), 3.28-3.31 (r, 1H), 3.33-3.41 (m, 2H), 3.51 (t, c=8.8
Hz, 1H), 3.56-3.61 (m, 3H), 3.71 (dd, J=4.0 & 9.2 Hz, 1H),
3.97-4.08 (m, 4H), 4.14 (d, J=9.6 Hz, 1H), 4.25 (dd, J=5.6 &
11.2 Hz, 1H), 4.41 (d, J=10.0 Hz, 1H), 6.80 (d, J=8.8 Hz, 2H),
7.07-7.3 (m, 6H), 7.23 (d, J=8.4 Hz, 1H), 7.35 (d, J=7.6 Hz,
2H)
[0632] (ES) m/z 582.0 (M+H).
EXAMPLE 85
Azetidin-1-yl-(3-{(2R,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-
-3,4,6-trihydroxy-tetrahydro-pyran-2-ylmethoxy}-phenyl)-methanone
##STR00100##
[0634] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.38 (t, J=7.2
Hz, 3H), 2.29-2.33 (m, 2H), 3.29-3.31 (m, 1H), 3.49 (t, J=8.8 Hz,
1H), 3.56 (t, J=9.2 Hz, 1H), 3.69-3.72 (m, 1H), 3.97-4.07 (m, 4H),
4.13-4.33 (m, 6H), 4.48 (d, J=11.2 Hz, 1H), 6.80 (d, J=8.8 Hz, 2H),
7.09 (d, J=8.8 Hz, 2H), 7.12 (dd, J=2.0 & 8.4 Hz, 1H),
7.19-7.26 (m, 4H), 7.34-7.38 (m, 2H)
[0635] MS (ES) m/z 568.1 (M+H).
EXAMPLE 86
4-{(2R,3S,4R,5R,6S)-6-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydro-
xy-tetrahydro-pyran-2-ylmethoxy}-benzamide
##STR00101##
[0637] The title compound was prepared in an analogous procedure as
described in example 120.
[0638] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.37 (t, J=6.8
Hz, 3H), 3.28-3.30 (m, 1H), 3.51 (t, J=8.8 Hz, 1H), 3.59 (t, J=8.8
Hz, 1H), 3.70-3.73 (m, 1H), 3.96-4.03 (m, 4H), 4.12 (d, J=9.6 Hz,
1H), 4.25 (dd, J=5.6 & 11.2 Hz, 1H), 4.42 (d, J=11.6 Hz, 1H),
6.79 (d, J=8.8 Hz, 2H), 7.05 (d, J=8.8 Hz, 2H), 7.10 (d, J=8.4 Hz,
2H), 7.23 (d, J=8.4 Hz, 1H), 7.26 (S, 1H), 7.35 (d, J=8.0 Hz, 1H),
7.85 (d, J=8.8 Hz, 2H).
[0639] MS (ES) m/z 528.3(M+H).
EXAMPLE 87
In Vitro Assays
[0640] The inhibitory effect on the sodium-dependent glucose
cotransporter SGLT, SGLT1 and SGLT2, of compounds of formula I may
be demonstrated using the following test procedures:
[0641] The ability of the substances to inhibit the SGLT-2 activity
may be demonstrated in a test set-up in which a CHO-K1 cell line
(ATCC No. CCL 6 1) or alternatively an HEK293 cell line (ATCC No.
CRL-1573), which is stably transfected with an expression vector
pZeoSV (Invitrogen, EMBL accession number L36849), which contains
the cDNA for the coding sequence of the human sodium glucose
cotransporter 2 (Genbank Ace. No.NM.sub.--003041) (CHO-hSGLT2 or
HEK-hSGLT2). These cell lines transport 14 C-labelled
alpha-methyl-glucopyranoside (14 C-AMG, Amersham) into the interior
of the cell in sodium-dependent manner.
[0642] The SGLT-2 assay is carried out as follows: CHO-hSGLT2 cells
are cultivated in Ham's F12 Medium (BioWhittaker) with 10% foetal
calf serum and 250 .mu.g/mL zeocin (Invitrogen), and HEK293-hSGLT2
cells are cultivated in DMEM medium with 10% foetal calf serum and
250 .mu.g/mL zeocin (Invitrogen). The cells are detached from the
culture flasks by washing twice with PBS and subsequently treating
with trypsin/EDTA. After the addition of cell culture medium the
cells are centrifuged, resuspended in culture medium and counted in
a Casy cell counter. Then 40,000 cells per well are seeded into a
white, 96-well plate coated with poly-D-Iysine and incubated
overnight at 37.degree. C., 5% CO2. The cells are washenwice with
250 .mu.l of assay buffer (Hanks Balanced Salt Solution, 137 mM
NaCl, 5.4 mM KCl, 2.8 mM CaCl2, 1.2 mM MgSO4 and 10 mM HEPES (pH
7.4), 50 .mu.g/mL of gentamycin). 250 .mu.l of assay buffer and 5
.mu.l of test compound are then added to each well and the plate is
incubated for a further 15 minutes in the incubator. 5 .mu.l of 10%
DMSO are used as the negative control. The reaction is started by
adding 5 .mu.l of 14 C-AMG (0.05 .mu.Ci) to each well. After 2
hours' incubation at 37.degree. C., 5% CO2, the cells are washed
again with 250 .mu.l of PBS (200C) and then lysed by the addition
of 25 .mu.l of 0.1 N NaOH (5 min. at 37.degree. C.). 200 .mu.l of
MicroScint20 (Packard) are added to each well and incubation is
continued for a further 20 min at 37.degree. C. After this
incubation the radioactivity of the 14 C-AMG absorbed is measured
in a Topcount (Packard) using a 14 C scintillation program.
[0643] To determine human SGLT1 inhibitory activity, an analogous
test was set up in which the cDNA for hSGLTI (Genbank Ace. No.
NM000343) instead of hSGLT2 cDNA is expressed in CHO-K1 or HEK293
cells. The uptake assay buffer in the case of the hSGLT1 assay
contains 10 mM HEPES, 5 mM Tris, 140 mM NaCl, 2 mM KCl, 1 mM
CaCl.sub.2, and 1 mM MgCl.sub.2, pH 7.4 containing 0.5 mM of
.alpha.-methyl-D-glucopyranoside (AMG), 10 .mu.M of
[.sup.14C]-.alpha.-methyl-D-glucopyranoside and different inhibitor
concentrations.
[0644] The compounds according to the invention may for example
have IC.sub.50 values for SGLT2 inhibition below 1000 nM,
particularly below 100 nM, most preferably below 10 nM. The
compounds according to the invention may also have SGLT1 inhibitory
activity.
[0645] The title compounds of the above Examples were evaluated in
the above described assay and the results of which are collated in
Table 1.
TABLE-US-00001 TABLE 1 SGLT2 IC.sub.50 nM SGLT1 IC.sub.50 nM
Example Number (n = 1-4) (n = 1-4) 8 85 -- 10 20 <1000 11 60
<1000 15 65 -- 23 36 -- 24 57 -- 25 7 <50 26 12 <50 27 6
<50 36 6 -- 37 3 <50 40 13 <50 47 14 <50 50 8 <50 61
28 -- 67 9 -- 69 28 -- 77 61 -- 78 42 <100 80 13 <100 83 72
-- 84 11 -- 85 9 --
[0646] It can be seen that the compounds of the invention are
useful as inhibitors of SGLT2 and therefore useful in the treatment
of diseases and conditions mediated by SGLT2 such as the metabolic
disorders disclosed herein.
[0647] It will be understood that the invention has been described
by way of example only and modifications may be made whilst
remaining within the scope and spirit of the invention.
* * * * *